CN106977441A - A kind of preparation method of R diphenylprolinols - Google Patents
A kind of preparation method of R diphenylprolinols Download PDFInfo
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- CN106977441A CN106977441A CN201710331151.9A CN201710331151A CN106977441A CN 106977441 A CN106977441 A CN 106977441A CN 201710331151 A CN201710331151 A CN 201710331151A CN 106977441 A CN106977441 A CN 106977441A
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- diphenylprolinols
- reaction
- proline
- preparation
- methanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/08—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 hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation method of R diphenylprolinols, it is related to technical field of organic synthesis, the present invention is using D proline as raw material, first D proline methyl ester hydrochlorides are made with methanol and thionyl chloride through esterification and salt-forming reaction, then through grignard reaction R diphenylprolinols are made with the RMgBr of bromobenzene；Methanol does reaction reagent and reaction dissolvent simultaneously, and unreacted methanol and solvents tetrahydrofurane can be with recoveries, so as to reduce production cost；The average purity of product R diphenylprolinols reaches 99.2%, and average total recovery reaches 70%, it is adaptable to industrialized production.
Description
Technical field：
The present invention relates to technical field of organic synthesis, and in particular to a kind of preparation method of R- diphenylprolinols.
Background technology：
Prolinol compound is a kind of important chiral reagent, is widely used in the asymmetric reduction of carbonyl, carbonyl
In a variety of asymmetric reactions such as asymmetric α alkylation, it can be applied in carboxylic acid Chiral's fractionation, R- diphenylprolinols are normal
The asymmetric reduction reaction for carbonyl is combined with boron compound.
Existing synthetic method, using D-PROLINE as raw material, successively with chloroacetic chloride, triethylamine and (BOC)2O reacts, finally
Reacted with phenyl-magnesium-bromide, extracted through ethyl acetate and target product R- diphenylprolinols are made, gross production rate is 46%.Shortcoming exists
In complex synthetic route, product yield is low.
The content of the invention：
The technical problems to be solved by the invention are to provide a kind of simple technique, the easy, mild condition of post processing, reaction
Cost is low, environmental pollution is small, product yield is high and the system of the good R- diphenylprolinols with suitable for industrialized production of purity
Preparation Method.
The technical problems to be solved by the invention are realized using following technical scheme：
A kind of preparation method of R- diphenylprolinols, including following preparation process：
(1) D-PROLINE is added in methanol, and thionyl chloride is added dropwise, back flow reaction is incubated after dripping off, after reaction terminates
Post-treated obtained D-PROLINE methyl ester hydrochloride；
(2) D-PROLINE methyl ester hydrochloride obtained above is added in tetrahydrofuran, then the bromobenzene grignard of existing system is added dropwise
Reagent, is incubated back flow reaction, and R- diphenylprolinol crude products are made through post processing after terminating in reaction, and crude product is again through ethanol and activity
Carbon decoloring is purified, and produces R- diphenylprolinol sterlings.
Reaction temperature is 60-80 DEG C, preferably 70-80 DEG C in the step (1).
The mol ratio of D-PROLINE and thionyl chloride, methanol is 1 in the step (1):1-2:10-15, preferably 1:1-
1.5:12-14。
The mol ratio of D-PROLINE methyl ester hydrochloride and bromobenzene, magnesium chips, tetrahydrofuran is 1 in the step (2):5-7:5-
7:5-9, preferably 1:5-6:5-5.5:7-8.
The beneficial effects of the invention are as follows：The present invention is first anti-through esterification with methanol and thionyl chloride using D-PROLINE as raw material
D-PROLINE methyl ester hydrochloride should be made with salt-forming reaction, then through grignard reaction R- diphenyl dried meat is made with the RMgBr of bromobenzene
Ammonia alcohol；Methanol does reaction reagent and reaction dissolvent simultaneously, unreacted methanol and solvents tetrahydrofurane can with recovery so that
Reduce production cost；And common synthetic methods need that the amino in D-PROLINE structure is protected and is deprotected, increase
Operation；The average purity of product R- diphenylprolinols reaches 99.2%, and average total recovery reaches 70%, it is adaptable to work
Industry metaplasia is produced.
Embodiment：
In order that the technical means, the inventive features, the objects and the advantages of the present invention are easy to understand, tie below
Specific embodiment is closed, the present invention is expanded on further.
Embodiment 1
250ml methanol is added in reaction bulb, 0.5mol D-PROLINEs, stirring is cooled to 10 DEG C, thionyl chloride is added dropwise
0.6mol (1.2eq), completion of dropping is warming up between 70-80 DEG C, and insulation reaction 2h under reflux state, the reaction time arrives, sampling
Detection, raw material has reacted, post-treated to obtain white solid D-PROLINE methyl ester hydrochloride 0.44mol, and loss on drying 0.18% is pure
Degree 98.2%, yield is 88.0%.
Tetrahydrofuran 250ml, 2.0mol (5eq) magnesium chips is put into reaction bulb, bromobenzene 2.0mol (5eq) is added dropwise, is added dropwise
Finish, insulation backflow 2h, return time is arrived, is cooled between 40-50 DEG C.Tetrahydrofuran is added in another reaction bulb
200ml, upper step crude product 0.4mol, then obtained RMgBr is instilled in reaction bulb, completion of dropping, insulation reaction 2h, sampling
Detection, it is qualified to react, post-treated to decolourize that white solid 0.328mol, purity 99.3%, loss on drying 0.18%, yield is made
For 82.0%.
Embodiment 2
250ml methanol is added in reaction bulb, 0.5mol D-PROLINEs, stirring is cooled to 10 DEG C, thionyl chloride is added dropwise
(2eq, completion of dropping is warming up between 70-80 DEG C 1.0mol, and insulation reaction 2h under reflux state, the reaction time arrives, sampling inspection
Survey, raw material has reacted, post-treated to obtain white solid D-PROLINE methyl ester hydrochloride 0.42mol, loss on drying 0.182% is pure
Degree 97.8%, yield is 84.0%.
Tetrahydrofuran 250ml, 2.4mol (6eq) magnesium chips is put into reaction bulb, bromobenzene 2.0mol (6eq) is added dropwise, is added dropwise
Finish, insulation backflow 2h, return time is arrived, is cooled between 40-50 DEG C.Tetrahydrofuran is added in another reaction bulb
200ml, upper step crude product 0.4mol, then obtained RMgBr is instilled in reaction bulb, completion of dropping, insulation reaction 2h, sampling
Detection, it is qualified to react, post-treated to decolourize that white solid 0.318mol, purity 99.1%, loss on drying 0.2%, yield is made
For 79.5%.
Embodiment 3
300ml methanol is added in reaction bulb, 0.5mol D-PROLINEs, stirring is cooled to 10 DEG C, thionyl chloride is added dropwise
0.6mol (1.2eq), completion of dropping is warming up between 70-80 DEG C, and insulation reaction 2h under reflux state, the reaction time arrives, sampling
Detection, raw material react, post-treated to obtain white solid D-PROLINE methyl ester hydrochloride 0.438mol, loss on drying 0.16%,
Purity 97.9%, yield is 87.6%.
Tetrahydrofuran 300ml, 2.0mol (5eq) magnesium chips is put into reaction bulb, bromobenzene 2.0mol (5eq) is added dropwise, is added dropwise
Finish, insulation backflow 2h, return time is arrived, is cooled between 40-50 DEG C.Tetrahydrofuran is added in another reaction bulb
250ml, upper step crude product 0.4mol, then obtained RMgBr is instilled in reaction bulb, completion of dropping, insulation reaction 2h, sampling
Detection, it is qualified to react, post-treated to decolourize that white solid 0.326mol, purity 99.2%, loss on drying 0.17%, yield is made
For 81.5%.
The general principle and principal character and advantages of the present invention of the present invention has been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the simply explanation described in above-described embodiment and specification is originally
The principle of invention, without departing from the spirit and scope of the present invention, various changes and modifications of the present invention are possible, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (5)
1. a kind of preparation method of R- diphenylprolinols, it is characterised in that including following preparation process：
(1) D-PROLINE is added in methanol, and thionyl chloride is added dropwise, back flow reaction is incubated after dripping off, reacted after terminating after
D-PROLINE methyl ester hydrochloride is made in processing；
(2) D-PROLINE methyl ester hydrochloride obtained above is added in tetrahydrofuran, then is added dropwise the bromobenzene RMgBr of existing system,
Back flow reaction is incubated, R- diphenylprolinol crude products are made through post processing after terminating in reaction, and crude product is de- through ethanol and activated carbon again
Colour purity, produces R- diphenylprolinol sterlings.
2. the preparation method of R- diphenylprolinols according to claim 1, it is characterised in that：It is anti-in the step (1)
It is 60-80 DEG C to answer temperature, and the mol ratio of D-PROLINE and thionyl chloride, methanol is 1:1-2:10-15.
3. the preparation method of R- diphenylprolinols according to claim 2, it is characterised in that：It is anti-in the step (1)
Answer preferred 70-80 DEG C of temperature, D-PROLINE and thionyl chloride, the mol ratio preferably 1 of methanol:1-1.5:12-14.
4. the preparation method of R- diphenylprolinols according to claim 1, it is characterised in that：D- in the step (2)
The mol ratio of proline methyl ester hydrochloride and bromobenzene, magnesium chips, tetrahydrofuran is 1:5-7:5-7:5-9.
5. the preparation method of R- diphenylprolinols according to claim 4, it is characterised in that：D- in the step (2)
Proline methyl ester hydrochloride and bromobenzene, magnesium chips, the mol ratio preferably 1 of tetrahydrofuran:5-6:5-5.5:7-8.
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| CN201710331151.9A CN106977441A (en) | 2017-05-11 | 2017-05-11 | A kind of preparation method of R diphenylprolinols |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645813A (en) * | 2020-12-25 | 2021-04-13 | 蚌埠中实化学技术有限公司 | Preparation method of (R) -3-cyclohexenecarboxylic acid |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101724016A (en) * | 2008-10-28 | 2010-06-09 | 上海医药工业研究院 | Peptide compound and preparation method and application thereof |
| CN105618135A (en) * | 2016-01-10 | 2016-06-01 | 沧州普瑞东方科技有限公司 | Preparation method of chiral CBS catalyst |
-
2017
- 2017-05-11 CN CN201710331151.9A patent/CN106977441A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101724016A (en) * | 2008-10-28 | 2010-06-09 | 上海医药工业研究院 | Peptide compound and preparation method and application thereof |
| CN105618135A (en) * | 2016-01-10 | 2016-06-01 | 沧州普瑞东方科技有限公司 | Preparation method of chiral CBS catalyst |
Non-Patent Citations (1)
| Title |
|---|
| SUSANN PAUL ET AL.: "A Novel Fluorinated Gold(I) N-Heterocyclic Carbene Complex: Exploiting Fluorine Stereoelectronic Effects To Control Molecular Topology", 《ORGANOMETALLICS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112645813A (en) * | 2020-12-25 | 2021-04-13 | 蚌埠中实化学技术有限公司 | Preparation method of (R) -3-cyclohexenecarboxylic acid |
| CN112645813B (en) * | 2020-12-25 | 2023-05-05 | 安徽英特美科技有限公司 | Preparation method of (R) -3-cyclohexene carboxylic acid |
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Application publication date: 20170725 |