CN108440240A - A kind of synthetic method of high-purity (S)-(+) -2- amylalcohols - Google Patents
A kind of synthetic method of high-purity (S)-(+) -2- amylalcohols Download PDFInfo
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- CN108440240A CN108440240A CN201810202619.9A CN201810202619A CN108440240A CN 108440240 A CN108440240 A CN 108440240A CN 201810202619 A CN201810202619 A CN 201810202619A CN 108440240 A CN108440240 A CN 108440240A
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- amylalcohols
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/09—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis
- C07C29/095—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by hydrolysis of esters of organic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/88—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound
- C07C29/92—Separation; Purification; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification of at least one compound by a consecutive conversion and reconstruction
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/18—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group
- C07C67/20—Preparation of carboxylic acid esters by conversion of a group containing nitrogen into an ester group from amides or lactams
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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 synthetic methods of 2 amylalcohol of high-purity (S) (+), which is characterized in that puts into 2 amylalcohols phthalic anhydride, triethylamine is slowly added dropwise, react maturation；It is quenched after reaction, is added in n-hexane, obtains white crystals DL Ester；It adds it in acetone, (S) () 1 phenyl ethylamine is added dropwise；It filters, filter cake recrystallization obtains white crystals D Ester L Amine；It adds it in dilute hydrochloric acid solution, is extracted with dichloromethane, obtain white crystals (+) Ester；It adds it in NaOH solution and is layered, water layer is extracted with DCM again, obtains crude product；Crude product obtains 2 amylalcohol of high-purity (S) (+) by air-distillation.The present invention is using the acetone recrystallization of cheap low toxicity, and raw material is cheap and easy to get, and reaction condition is mild, dangerous small, and easy to operate, reaction is easily controllable, is suitable for industrialized production.
Description
Technical field
The present invention relates to a kind of preparation methods being used for high-purity (S)-(+) -2- amylalcohols, belong to Photobiology activity and doctor
The synthesis technical field of medicine intermediate.
Background technology
Be widely used in terms of the synthesis of bioactive molecule and medicine intermediate with chiral micromolecular compound it is general,
Researching value is very high or even some chiral micromolecular compounds have been realized in industrialization mass production.And the present invention opens
Chiral micromolecular compound (S)-(+) -2- amylalcohols issued are closed in the exploitation of bioactive molecule and Medicine intermediate
Good utilization has also been obtained at aspect.Therefore, develop it is a kind of synthesis high-purity (S)-(+) -2- amylalcohols and can realize industry
The process of change is extremely important.
(S)-(+) synthesis of -2- amylalcohols, according to the literature, some are used based on industrial cheap raw material 2 pentanone
Then raw material was also synthesized originally by the asymmetric hydrogenation of selectivity, but the cost of catalyst is very high, and research is in milligram grade
Laboratory scale, be not suitable for industrialized production (Tetrahedron Asymmetry, 2002, v01.13, #9p.971-974)；
In addition some scholars use the raw material n-pentene being industrially easy to get for main material, and then C=C oxidations become epoxide, most
Selective reduction open loop is carried out by chiral catalyst afterwards, obtains purpose thing, but is also expensive there are catalyst and receives
The low-down problem of rate is not suitable for industrialized production (EP1582511A2.2005).
Invention content
It is simple and to environment friend that problem to be solved by this invention is to provide a kind of low cost, high yield, purifying process
Good is suitable for industrialized synthesis high-purity (S)-(+) -2- amylalcohol processes.
To solve the above-mentioned problems, the present invention is using 2- amylalcohols, phthalic anhydride and (S)-(-)-being industrially easy to get
The cheap raw material such as 1- phenyl ethylamines synthesizes (S)-(+) -2- amylalcohols by the method for chemical resolution, and then crude product is steamed using decompression
It evaporates to obtain the product of high-purity.Its chemical equation is as follows：
The present invention a specific technical solution be：A kind of synthetic method of high-purity (S)-(+) -2- amylalcohols, feature
It is, includes the following steps：
The first step：Phthalic anhydride is put into 2- amylalcohols and is mixed；
Second step：Triethylamine is slowly added dropwise in the mixture, there is exothermic phenomenon, after completion of dropwise addition, reacts maturation；
Third walks：It is quenched using dilute hydrochloric acid after reaction, post-processing is extracted using dichloromethane, is then used organic
It is mutually filtered after drying, adds in n-hexane, cooling crystallization, obtain white crystals DL-Ester；
4th step：White crystals DL-Ester is added in acetone, stirs, under room temperature, then (S)-(-)-is added dropwise
1- phenyl ethylamines generate white solid and generate, after dripping, return stirring maturation；
5th step：After reaction, be cooled to room temperature, filter, filter cake uses acetone recrystallization, by repeatedly heat it is outstanding wash come
Impurity is removed, is dried under reduced pressure to obtain white crystals D-Ester-L-Amine；
6th step：White crystals D-Ester-L-Amine is added in dilute hydrochloric acid solution, is stirred；Then dichloromethane is used
White crystals (+)-Ester is obtained after alkane extraction, dry, reduced pressure drying；
7th step：White crystals (+)-Ester is added in NaOH solution, after being heated to reflux, is cooled to room temperature, point
Layer, water layer are extracted twice with DCM again, merge organic phase, and drying is concentrated to give crude product；
8th step：By crude product by air-distillation, 117~118 DEG C of fractions are collected, high-purity (S)-(+) -2- penta is obtained
Alcohol.
Preferably, the first step carries out under the conditions of 20 DEG C~25 DEG C.
Preferably, triethylamine is added dropwise in the second step to carry out under the conditions of 45~50 DEG C；Maturation is in 65~70 DEG C of items
It is reacted 3 hours under part.
Preferably, the molar ratio of the phthalic anhydride, 2- amylalcohols and triethylamine is 1: 1: 1.
Preferably, the equivalent concentration of dilute hydrochloric acid is 1N in the third step；The volume ratio of n-hexane and dichloromethane is 1:
1。
Preferably, the maturation time is 1 hour in the 4th step.
Preferably, the 5th step recrystallization the specific steps are：Filter cake acetone is outstanding to be washed once, is dried under reduced pressure；It is dry
Afterwards, then with acetone reflux 1 hour, outstanding to wash primary, it is cooled to room temperature, filters, filter cake is washed once with acetone again.
Preferably, the time being heated to reflux in the 7th step is 3 hours.
Preferably, the G/C content of high-purity (S)-(+) -2- amylalcohols that the 8th step obtains be 99.5%, optical activity be+
13.8deg, ee value are 99.5%.
Compared with prior art, beneficial effects of the present invention are：
All it is industrialization product 1. the synthesis material that the present invention uses is cheap and easy to get, reaction condition is mild, dangerous
Small, easy to operate, reaction is easily controllable, and yield is up to 80% or more, is suitable for industrialized production；
2. present invention employs cheap and less toxic organic solvent-acetone recrystallization, purpose thing need to only pass through air-distillation
High purity product is obtained, the chiral ee values of product reach 99% or more.
Specific implementation mode
In order to make the present invention more obvious and understandable, it is hereby described in detail below with preferred embodiment.
Embodiment
A kind of process of synthesis high-purity (S)-(+) -2- amylalcohols, specific implementation step are as follows：
(1) prepare 10L reaction kettles and be first separately added into 2- amylalcohols (2.5L, 23.3mol), phthalic acid under room temperature
Acid anhydride (3.45kg, 23.3mol), stirring；
(2) under the conditions of 45~50 DEG C, triethylamine (1.18kg, 11.6mol) is slowly added dropwise, there is exothermic phenomenon, knot is added dropwise
Shu Hou, reaction maturation 3 hours under the conditions of 65~70 DEG C；
(3) after reaction, reaction solution is transferred in the reaction kettle of 45L, then is slowly added into the 1N dilute hydrochloric acid of 12L, stirred
It mixes, dichloromethane extraction (5L × 2) is added, merge organic phase, magnesium sulfate drying is filtered, and filtrate is blended into 10L n-hexanes,
It is cooled to 0 DEG C, is stood overnight, there are a large amount of solids to be precipitated, filters, is dried under reduced pressure to obtain 4.6kg white crystals DL-Ester；
(4) 1.55kg white crystals DL-Ester is added in 5.5L acetone, stirs, under room temperature, then is added dropwise
(S)-(-) -1- phenyl ethylamines (800g, 6.6mol) has a large amount of white crystals to occur, and reflux 1 hour is reheated after dripping；
(5) after reaction, it is cooled to room temperature, filters, filter cake is washed with 1.28L acetone is outstanding again, is dried under reduced pressure to obtain 894G knots
It is brilliant；4.5L acetone being added in this crystal again, be heated to reflux 1 hour, be cooled to room temperature, filters, filter cake is washed with 1L acetone is outstanding again,
It is dried under reduced pressure, obtains 737G white crystals D-Ester-L-Amine；
(6) 2.2kg white crystals D-Ester-L-Amine is added in 12L 1N HCl solutions, is stirred 1 hour, then
It is extracted (5L × 2) with dichloromethane, merges organic phase, magnesium sulfate drying, filtering is concentrated under reduced pressure to give 1.44kg white knots
Crystalline substance (+)-Ester；
(7) NaOH (700g, 17.5mol) is added to 2L H2In O, then stirring and dissolving adds 1.44kg white knots
Crystalline substance (+)-Ester heats 80~95 DEG C, reacts 3 hours；After reaction, it is cooled to room temperature, is layered, water layer uses dichloromethane again
Alkane extracts (2L × 2), merges organic phase, dry, is concentrated under reduced pressure, obtains 500G crude products (S)-(+) -2- amylalcohols；
(8) 500G crude products are subjected to air-distillation, collect 117~118 DEG C of fractions, obtains 435G sterlings (S)-(+) -2- penta
Alcohol, yield 81%, after testing, product G C purity are 99.5%, and proportion (20/20) is 0.8104, and flexion rate n20/D is
1.4063, optical activity is+13.8deg, and ee values are 99.5%.
The nuclear magnetic resonance data of product obtained above is as follows：
6=3.76~83.87 (1H, m) 1H-NMR (CDCl3,400MHz, δ ppm), 1.36~1.51 (4H, m), 1.18
(3H, d, J=6.0Hz), 0.93 (3H, t, J=6.9Hz).
Claims (9)
1. a kind of synthetic method of high-purity (S)-(+) -2- amylalcohols, which is characterized in that include the following steps：
The first step：Phthalic anhydride is put into 2- amylalcohols and is mixed；
Second step：Triethylamine is slowly added dropwise in the mixture, there is exothermic phenomenon, after completion of dropwise addition, reacts maturation；
Third walks：It is quenched using dilute hydrochloric acid after reaction, post-processing is extracted using dichloromethane, then using organic relevant
Filtering, adds in n-hexane, cooling crystallization, obtains white crystals DL-Ester after dry；
4th step：White crystals DL-Ester is added in acetone, stirs, under room temperature, then (S)-(-) -1- benzene is added dropwise
Ethamine generates white solid and generates, after dripping, return stirring maturation；
5th step：After reaction, it is cooled to room temperature, filters, filter cake uses acetone recrystallization, is hanged and is washed to remove by repeatedly heat
Impurity is dried under reduced pressure to obtain white crystals D-Ester-L-Amine；
6th step：White crystals D-Ester-L-Amine is added in dilute hydrochloric acid solution, is stirred；Then extracted with dichloromethane
Take, dry, be concentrated under reduced pressure it is dry after obtain white crystals (+)-Ester；
7th step：White crystals (+)-Ester is added in NaOH solution, after being heated to reflux, is cooled to room temperature, is layered, water
Layer is extracted twice with DCM again, merges organic phase, and drying is concentrated to give crude product；
8th step：By crude product by air-distillation, 117~118 DEG C of fractions are collected, high-purity (S)-(+) -2- amylalcohols are obtained.
2. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that the first step exists
It is carried out under the conditions of 20 DEG C~25 DEG C.
3. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that in the second step
Triethylamine is added dropwise to carry out under the conditions of 45~50 DEG C；Maturation is reacted 3 hours under the conditions of 65~70 DEG C.
4. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that the O-phthalic
The molar ratio of acid anhydrides, 2- amylalcohols and triethylamine is 1: 1: 1.
5. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that in the third step
The equivalent concentration of dilute hydrochloric acid is 1N；The volume ratio of n-hexane and dichloromethane is 1: 1.
6. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that in the 4th step
The maturation time is 1 hour.
7. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that the 5th step weight
Crystallization the specific steps are：Filter cake acetone is outstanding to be washed once, is dried under reduced pressure；It is outstanding to wash one after drying, then with acetone reflux 1 hour
It is secondary, it is cooled to room temperature, filters, filter cake is washed once with acetone again.
8. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that in the 7th step
The time being heated to reflux is 3 hours.
9. the synthetic method of high-purity (S)-(+) -2- amylalcohols as described in claim 1, which is characterized in that the 8th step obtains
The G/C content of high-purity (S)-(+) -2- amylalcohols arrived is 99.5%, and optical activity is+13.8deg, and ee values are 99.5%.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005009935A1 (en) * | 2003-07-25 | 2005-02-03 | Postech Foundation | Method of preparation of optically active alcohols |
| EP1582511A3 (en) * | 2004-03-31 | 2006-03-29 | Daiso Co., Ltd. | Process for preparing secondary alcohol |
| CN102408313A (en) * | 2011-10-20 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method of R-3-butyne-2-alochol |
-
2018
- 2018-03-12 CN CN201810202619.9A patent/CN108440240A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005009935A1 (en) * | 2003-07-25 | 2005-02-03 | Postech Foundation | Method of preparation of optically active alcohols |
| EP1582511A3 (en) * | 2004-03-31 | 2006-03-29 | Daiso Co., Ltd. | Process for preparing secondary alcohol |
| CN102408313A (en) * | 2011-10-20 | 2012-04-11 | 浙江普洛康裕制药有限公司 | Preparation method of R-3-butyne-2-alochol |
Non-Patent Citations (3)
| Title |
|---|
| LIWEI REN 等: "A green resolution–separation process for aliphatic secondary alcohols", 《TETRAHEDRON: ASYMMETRY》 * |
| 张道俊: "不对称中卤代烃的合成研究", 《中国优秀硕士学位论文全文数据库》 * |
| 许家喜: "光学活性反式1-(4-烷基环己基)醇的制备", 《有机化学》 * |
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Application publication date: 20180824 |