CN106699626B - A kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme - Google Patents
A kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme Download PDFInfo
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The present invention provides a kind of preparation methods of mixed 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate: 1) willR- 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is dissolved in mixed solvent and obtains solution；2) the first sour solid is added into solution described in step 1) or solution flows back；3) solution of the second acid is added after the completion of reaction, organic phase is collected in liquid separation；4) organic phase is concentrated, and the residue obtained after precipitation is dissolved in ethyl alcohol or methanol, hydroxide aqueous solution is added, salts out mixed 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, filters, is drying to obtain.The present invention also providesSThe preparation process of -2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid makes its yield by 30% raising to 40% or so, while reducing the generation of waste, with good economic efficiency and social benefit.
Description
Technical field
The invention belongs to Pharmaceutical Analysis technical fields, retrieve 2- hydroxyl by recycling by-product more particularly to a kind of
The preparation method of base -3- methoxyl group -3,3- diphenylprop hydrochlorate raceme.
Background technique
S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid is the important centre for synthesizing ambrisentan (ambrisentan)
Body.
Ambrisentan is a kind of endothelin-receptor antagonists developed by Myogen company, the U.S., trade name
Letairis takes orally for treating pulmonary hypertension.Pulmonary hypertension is a kind of very high disease of lethality, can lead to the heart
The gradually decline of lung function, and still lack effective therapeutic agent at present.Endothelin -1 (ET-1) plays vessel retraction non-
Normal important role generates vessel retraction phenomenon when ET-1 is in conjunction with Endothelin A type (ETA) receptor；Ambrisentan is that have
Highly selective endothelin receptor A antagonist, can vessel retraction caused by potent inhibition Endothelin, bioavilability is high,
For long half time, it can be achieved that being administered orally 1 time a day, curative effect is substantially better than non-selective endothelin-receptor antagonists.
The synthetic method of known S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, as patent CN95195655 is retouched
It states, is that 3,3- diphenyl -2,3- epoxy group propionic ester adjusts reaction mixture pH value to acidity, You Jirong after open loop, hydrolysis
Agent is extracted, and purifying is obtained 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, split with L-PROLINE methyl ester hydrochloride,
After being filtered to remove R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt, filtrate obtains after post treatment
S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid.Due to S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid and R-2- hydroxyl
Base -3- methoxyl group -3,3- diphenyl-propionic acid equivalent exists, and the theoretical yield of resolution reaction is 50%, and actual recovery is about 30%,
Yield is low, at the same by-product R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt according to waste into
Row processing, increases cost.
Method to general hydroxy compounds racemization is mostly to mix compound with water, and acid is added, brings it about SN1Turn
Change, but there are two phenyl ring in R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid structure, hydrophobicity is very strong, almost insoluble
S directly occurs in water for Yu ShuiN1It converts extremely difficult；R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE first
Although ester salt can be dissolved in water, it is easy to free R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid after the acid addition,
The research recycled to R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid or derivatives thereof is had no so far.
Summary of the invention
The object of the present invention is to provide a kind of preparation sides of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme
Method, this method are that R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is carried out simple and direct processing, are obtained
To 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme.This method can make 2- hydroxy-3-methoxy -3,3- hexichol
By-product in base propionate split process continues to split, to make S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid
Yield improve to 40% or so, while reducing the generation of waste.
To achieve the above object, the present invention provides the following technical solution:
A kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme, which comprises
1) R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is dissolved in mixed solvent, obtained
R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salting liquid；
2) into R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salting liquid described in step 1)
The solid or solution that the first acid is added flow back；
3) make pH value 1~2 in the solution that the second acid is added in step 2) after reaction, organic phase is collected in liquid separation；
4) concentration step 3) obtained organic phase, and the residue obtained after desolventizing is dissolved in ethyl alcohol or methanol, it is added
2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme is precipitated in hydroxide aqueous solution, and filtering is drying to obtain；
Wherein,
The mixed solvent is the mixture of organic ether and water, and the organic ether is selected from methyl tertiary butyl ether(MTBE), ether, 2-
The volume ratio of methyltetrahydrofuran, organic ether and water is 1:10~5:1.
First acid is selected from the hydration of sulfuric acid, substituted or unsubstituted benzene sulfonic acid and substituted or unsubstituted benzene sulfonic acid
Object；The mole of first acid is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole
0.1%-10%；
Second acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and acetic acid.
In an embodiment according to the present invention, R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-
Byproduct of the proline methyl ester salt from the technique for preparing S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid.
In an embodiment according to the present invention, the volume ratio of the organic ether and water is 1:8~3:1；
In an embodiment according to the present invention, the mole of first acid is hydroxy-3-methoxy -3 R-2-,
3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole 1%-5%.
In an embodiment according to the present invention, the mole that the described second sour mole converts into proton is R-2-
0.9-1.2 times of hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole.Preferably, described
The mole that diacid mole converts into proton is that R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is rubbed
1.02 times of that amount.
In an embodiment according to the present invention, the hydroxide be selected from selected from lithium hydroxide, sodium hydroxide or
One of potassium hydroxide is a variety of, and the mole of hydroxide is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-
0.9-1.2 times of proline methyl ester salt mole；Preferably, the mole of the hydroxide is R-2- hydroxyl -3- methoxy
1.0 times of base -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole.
The present invention also provides a kind of preparation process of S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, the preparations
Technique includes method as described above.
In an embodiment according to the present invention, the preparation process includes that will split hydroxy-3-methoxy -3 2-,
3- diphenylprop hydrochlorate raceme obtains by-product R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt
It is recycled according to method as described above.
The present inventor has found under study for action, the acid and mixed solvent of catalytic amount is used in racemization, in faintly acid
Under the conditions of, R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is dissolved in water and does not dissolve in organic phase,
Racemization first occurs in water, while a small amount of free 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid out is enriched with to organic phase,
Reduce side reaction；This method recycling preparation 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid purity salt 99.0% with
On, meet internal control quality standard, can carry out splitting preparation S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, to make
The yield of S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid is greatly improved.
The method of the present invention is recycled by-product by optimization method, makes S-2- hydroxy-3-methoxy -3,3- bis-
The yield of phenylpropionic acid is improved by 30% to 40% or so, while reducing the generation of waste, have good social benefit and
Economic benefit.
Specific embodiment
Present invention will be further explained by specific examples below, it should be understood, however, that, these embodiments are only
It is used, is but should not be understood as present invention is limited in any form for specifically describing in more detail.
Embodiment 1
230g diphenyl -2,3- epoxy group propionic ester is dissolved in 600mL methanol, stirring at normal temperature dissolution is added 5.7g pairs
Toluenesulfonic acid after 20-25 DEG C of stirring 0.5h, is heated to flowing back, then instills 10% sodium hydroxide 800mL, returns after completion of dropwise addition
Stream stirring 1.5h, is added 1000ml water after methanol is concentrated, is placed under ice bath after stirring 0.5h and filters, and solid is washed with cold water again,
60 DEG C of forced air dryings.
1h, filtering is mixed in obtained solid and 300ml ethyl alcohol and 600ml petroleum ether, and 60 DEG C of forced air dryings obtain 2- hydroxyl
Base -3- methoxyl group -3,3- diphenyl-propionic acid sodium, white solid about 160g.
By 100g 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid sodium be added methyl tertiary butyl ether(MTBE) (MTB, 2000ml) and
In methanol (40ml), then be added 56.1g L-PROLINE methyl ester hydrochloride (0.34mol), stirring at normal temperature 6h, standing, crystallization,
Filtering, filter cake and filtrate are handled respectively.
400ml water is added to filtrate, adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer uses MTB again
(400ml) extraction, merges organic layer, is washed with 800ml, and saturation NaCl solution washs organic layer, and anhydrous sodium sulfate is dry, dense
Then contracting is recrystallized with ethyl acetate 80ml and hexamethylene 500ml, is stood overnight.Hydroxy-3-methoxy -3 S-2- are filtered to obtain,
3- diphenyl-propionic acid 27.0g, yield 29.2%.
Filter cake 61.4g is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt, is added to it
300mL water and 300mL methyl tertiary butyl ether(MTBE), a hydration p-methyl benzenesulfonic acid 0.3g, temperature rising reflux 10 hours, are added 6mol/L hydrochloric acid
Organic phase is collected in 26mL, pH value of solution=1~2, liquid separation, is concentrated under reduced pressure, and ethyl alcohol 80mL dissolution is added, adds water 100mL, is added dropwise
10% sodium hydroxide solution 56mL, a large amount of white solids are precipitated, filter after stirring 0.5h under ice bath, 60 DEG C of forced air dryings.Gained
1h, filtering is mixed in solid and 60ml ethyl alcohol and 120ml petroleum ether, and 60 DEG C of forced air dryings obtain white solid about 33.1g.
By 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid sodium of recycling be added methyl tertiary butyl ether(MTBE) (MTB, 650ml) and
In methanol (130ml), 18.6g L-PROLINE methyl ester hydrochloride, stirring at normal temperature 6h, standing, crystallization, filtering, filtrate is then added
Middle addition 130ml water adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer is used MTB (300ml) to extract again, is associated with
Machine layer, saturation NaCl solution wash organic layer, and anhydrous sodium sulfate is dry, then concentration is recrystallized with ethyl acetate and hexamethylene,
It stands overnight.Filter solid S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid is crossed, about 8.4g, yield 9.1% (to throw for the first time
2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid sodium the meter of material).
Embodiment 2
210g diphenyl -2,3- epoxy group propionic ester is dissolved in 600mL methanol, stirring at normal temperature dissolution is added 5.2g pairs
Toluenesulfonic acid after 20-25 DEG C of stirring 0.5h, is heated to flowing back, then instills 10% potassium hydroxide solution 1000ml, completion of dropwise addition
Return stirring 1.5h afterwards is added 250ml water after methanol is concentrated, is placed under ice bath after stirring 0.5h and filters, solid is washed with cold water again
It washs, 60 DEG C of forced air dryings.
Obtained solid and 300ml methylene chloride stir 1h, filtering, and 60 DEG C of forced air dryings obtain 2- hydroxy-3-methoxy-
3,3- diphenyl-propionic acid potassium, white solid about 140g.
By 106g 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid potassium be added methyl tertiary butyl ether(MTBE) (MTB, 2000ml) and
In methanol (40ml), then be added 56.1g L-PROLINE methyl ester hydrochloride (0.34mol), stirring at normal temperature 6h, standing, crystallization,
Filtering, filter cake and filtrate are handled respectively.
400ml water is added in filtrate, adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer uses MTB again
(400ml) extraction, merges organic layer, is washed with 800ml, and saturation NaCl solution washs organic layer, and anhydrous sodium sulfate is dry, dense
Then contracting is recrystallized with ethyl acetate 80ml and hexamethylene 500ml, is stood overnight.Hydroxy-3-methoxy -3 S-2- are filtered to obtain,
3- diphenyl-propionic acid 28.3g, yield 30.6%.
Filter cake 59.2g is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt, Xiang Qijia
200mL water and 1000mL ether, 1mol/L sulfuric acid 0.2mL temperature rising reflux 8 hours, are added 5mol/L sulfuric acid 13.5mL, adjust molten
Organic phase is collected in liquid pH=1~2, liquid separation, is concentrated under reduced pressure, and methanol 80mL dissolution is added, adds water 100mL, 10% hydroxide is added dropwise
Potassium solution 69ml, a large amount of white solids are precipitated, and filter after stirring 0.5h under ice bath, 60 DEG C of forced air dryings.Obtained solid and 60ml
1h, filtering is mixed in ethyl alcohol and 120ml petroleum ether, and 60 DEG C of forced air dryings obtain white solid 33.2g.
Methyl tertiary butyl ether(MTBE) (MTB, 650ml) is added in 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid potassium of recycling
And in methanol (130ml), 17.6g L-PROLINE methyl ester hydrochloride is then added, stirring at normal temperature 6h is filtered after standing crystallization, is filtered
130ml water is added in liquid, adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer uses MTB (300ml) to extract again, merges
Organic layer, saturation NaCl solution wash organic layer, and anhydrous sodium sulfate is dry, then concentration is tied again with ethyl acetate and hexamethylene
Crystalline substance is stood overnight.Filter solid S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid 8.6g is crossed, yield 9.3% (to throw for the first time
2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid potassium the meter of material).
Embodiment 3
230g diphenyl -2,3- epoxy group propionic ester is dissolved in 600mL methanol, stirring at normal temperature dissolution is added 5.7g pairs
Toluenesulfonic acid after 20-25 DEG C of stirring 0.5h, is heated to flowing back, then instills 10% sodium hydroxide 800mL, returns after completion of dropwise addition
Stream stirring 1.5h, is added 1000ml water after methanol is concentrated, is placed under ice bath after stirring 0.5h and filters, and solid is washed with cold water again,
60 DEG C of forced air dryings.
1h, filtering is mixed in obtained solid and 300ml ethyl alcohol and 600ml petroleum ether, and 60 DEG C of forced air dryings obtain 2- hydroxyl
Base -3- methoxyl group -3,3- diphenyl-propionic acid sodium, white solid about 160g.
By 100g 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid sodium be added methyl tertiary butyl ether(MTBE) (MTB, 2000ml) and
In methanol (40ml), then be added 56.1g L-PROLINE methyl ester hydrochloride (0.34mol), stirring at normal temperature 6h, standing, crystallization,
Filtering, filter cake and filtrate are handled respectively.
400ml water is added to filtrate, adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer uses MTB again
(400ml) extraction, merges organic layer, is washed with 800ml, and saturation NaCl solution washs organic layer, and anhydrous sodium sulfate is dry, dense
Then contracting is recrystallized with ethyl acetate 80ml and hexamethylene 500ml, is stood overnight.Hydroxy-3-methoxy -3 S-2- are filtered to obtain,
3- diphenyl-propionic acid 25.7g, yield 27.8%.
Filter cake 64.2g is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt, is added to it
2000mL water and 200mL2- methyltetrahydrofuran, a hydration p-methyl benzenesulfonic acid 2.5g, temperature rising reflux 5 hours, are added glacial acetic acid
11.5g adjusts pH value of solution=1~2, and organic phase is collected in liquid separation, is concentrated under reduced pressure, and ethyl alcohol 80mL dissolution is added, adds water 100mL, drips
Add 10% lithium hydroxide solution 41mL, a large amount of white solids are precipitated, filter after stirring 0.5h under ice bath, 60 DEG C of forced air dryings.Institute
It obtains solid and 60ml ethyl alcohol and 1h, filtering is mixed in 120ml petroleum ether, 60 DEG C of forced air dryings obtain white solid about
30.9g。
By 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid lithium of recycling be added methyl tertiary butyl ether(MTBE) (MTB, 650ml) and
In methanol (130ml), 18.0g L-PROLINE methyl ester hydrochloride, stirring at normal temperature 6h, standing, crystallization, filtering, filter is then added
130ml water is added in liquid, adjusts pH=1~2 with the hydrochloric acid of 6N.Organic layer is separated, water layer uses MTB (300ml) to extract again, merges
Organic layer, saturation NaCl solution wash organic layer, and anhydrous sodium sulfate is dry, then concentration is tied again with ethyl acetate and hexamethylene
Crystalline substance is stood overnight.Filter solid S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid is crossed, about 8.7g, yield 9.4% is (with first
The secondary 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid sodium meter to feed intake).
Although present invention has been a degree of descriptions, it will be apparent that, do not departing from the spirit and scope of the present invention
Under the conditions of, the appropriate variation of each condition can be carried out.It is appreciated that the present invention is not limited to the embodiments, and it is attributed to right
It is required that range comprising the equivalent replacement of each factor.
Claims (9)
1. a kind of preparation method of 2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme, it is characterised in that: the side
Method includes:
1) R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt is dissolved in mixed solvent, obtains R-2-
Hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salting liquid；
2) it is added into R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salting liquid described in step 1)
The solid or solution of first acid flow back；
3) make pH value 1~2 in the solution that the second acid is added in step 2) after reaction, organic phase is collected in liquid separation；
4) concentration step 3) obtained organic phase, and the residue obtained after desolventizing is dissolved in ethyl alcohol or methanol, hydrogen-oxygen is added
2- hydroxy-3-methoxy -3,3- diphenylprop hydrochlorate raceme is precipitated in compound aqueous solution, and filtering is drying to obtain；
Wherein,
The mixed solvent is the mixture of organic ether and water, and the organic ether is selected from methyl tertiary butyl ether(MTBE), ether and 2- first
The volume ratio of base tetrahydrofuran, the organic ether and water is 1:10~5:1；
The hydrate of first acid selected from sulfuric acid, substituted or unsubstituted benzene sulfonic acid and substituted or unsubstituted benzene sulfonic acid；Institute
The mole for stating the first acid is R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole
0.1%~10%；
Second acid is selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and acetic acid；
R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE the methyl esters salt is from preparation S-2- hydroxyl -3- first
The byproduct of the technique of oxygroup -3,3- diphenyl-propionic acid.
2. the method as described in claim 1, which is characterized in that the volume ratio of the organic ether and water is 1:8~3:1.
3. method according to claim 1 or 2, which is characterized in that the mole of first acid is R-2- hydroxyl -3- first
Oxygroup -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole 1%-5%.
4. method according to claim 1 or 2, which is characterized in that the sour mole of described second converts into the mole of proton
It is 0.9~1.2 times of R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole.
5. method as claimed in claim 4, which is characterized in that the mole that the sour mole of described second converts into proton is R-
1.02 times of 2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole.
6. method according to claim 1 or 2, which is characterized in that the hydroxide is selected from lithium hydroxide, sodium hydroxide
Or one of potassium hydroxide or a variety of, the mole of hydroxide are R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acids -
0.9~1.2 times of L-PROLINE methyl esters salt mole.
7. method as claimed in claim 6, which is characterized in that the mole of the hydroxide is R-2- hydroxyl -3- first
1.0 times of oxygroup -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt mole.
8. a kind of preparation method of S-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid, which is characterized in that the preparation method
Including method such as according to any one of claims 1 to 7.
9. preparation method as claimed in claim 8, which is characterized in that mixed 2- hydroxy-3-methoxy -3,3- hexichol will be split
By-product R-2- hydroxy-3-methoxy -3,3- diphenyl-propionic acid-L-PROLINE methyl esters salt that base propionate obtains is wanted according to right
The recovery processing of method described in asking any one of 1~7, and obtained mixed 2- hydroxy-3-methoxy-will be recycled by described
3,3- diphenylprop hydrochlorate is split again.
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