CN104892356B - The preparation method of m-trifluoromethyl phenylpropanol - Google Patents
The preparation method of m-trifluoromethyl phenylpropanol Download PDFInfo
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- CN104892356B CN104892356B CN201510231545.8A CN201510231545A CN104892356B CN 104892356 B CN104892356 B CN 104892356B CN 201510231545 A CN201510231545 A CN 201510231545A CN 104892356 B CN104892356 B CN 104892356B
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- trifluoromethyl
- phenylpropanol
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- boron hydride
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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
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
Abstract
The invention discloses a kind of preparation method of m-trifluoromethyl phenylpropanol, it be in atent solvent, by reducing agent of boron hydride, lewis acid be co-catalyst, m-trifluoromethyl benzenpropanoic acid is reduced into m-trifluoromethyl phenylpropanol；Described atent solvent is one or both of methyl tertiary butyl ether(MTBE), isopropyl ether, methyltetrahydrofuran, tetrahydrofuran；The mol ratio of described boron hydride and m-trifluoromethyl benzenpropanoic acid is 1: 1~3: 1；Described boron hydride is sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride；The mol ratio of described lewis acid and m-trifluoromethyl benzenpropanoic acid is 1: 1~2: 1；Described lewis acid is methanesulfonic acid, the concentrated sulfuric acid, trifluoroacetic acid, zinc chloride, alchlor or zirconium chloride.Method reaction condition of the invention is gentle, simple to operate, post processing is simple, and especially security is higher, so as to be adapted to industrialized production.
Description
Technical field
The invention belongs to technical field of medical intermediate preparation, and in particular to a kind of preparation side of m-trifluoromethyl phenylpropanol
Method.
Background technology
Cinacalcet hydrochloride is a kind of Sensipar researched and developed by NPS Pharmaceuticals companies of the U.S.
（calcimimetics）.It can activate the calcium acceptor in parathyroid gland, so as to reduce parathormone（PTH）Secretion, adjust
The behavior of Parathyroid Calcium Receptor is saved, by strengthening sensitiveness of the acceptor to calcium level in blood flow, reduction parathyroid hormone,
The level of calcium, phosphorus and calcium-phosphorus compound.It is mainly used in the chronic kidney disease that treatment is dialysed（CKD）The Secondary cases first shape of patient
Other gland hyperfunction disease and the hypercalcinemia of parathyroid carcinoma patient.
The chemical name of cinacalcet hydrochloride is：(R)-N- (1- (naphthalene -1- bases) ethyl) -3- (3- (trifluoromethyl) phenyl)
Propyl- 1- amine hydrochlorates, structural formula is as follows：
。
M-trifluoromethyl phenylpropanol is an important intermediate for preparing cinacalcet hydrochloride, using its prepare hydrochloric acid west that
Jam mainly has two kinds of approach：One kind is that m-trifluoromethyl phenylpropanol first is oxidized into m-trifluoromethyl benzenepropanal, then again with
(R)-naphthalene -1- ethamine carries out reduction amination and obtains cinacalcet hydrochloride；It is another, it is made of first by m-trifluoromethyl phenylpropanol
Halides or sulphonic acid ester, are then alkylated reaction with (R)-naphthalene -1- ethamine again and obtain cinacalcet hydrochloride.
For the preparation of m-trifluoromethyl phenylpropanol, prior art discloses following several method：
（1）Using m-trifluoromethyl phenyl-bromide as raw material, through Sonogashira coupling reactions（European patent document
EP0194764A1）Or Heck coupling reactions（WO2006125026A2）Afterwards, then through steps such as catalytic hydrogenations it is made.
The deficiency of this kind of method is：Need using the higher catalyst of price, so that cause production cost higher, it is uncomfortable
Close industrialized production.
（2）Using m-trifluoromethylphenyl halide as raw material（Chinese patent literature CN102219661A）, it is anti-through grignard
Ying Hou, then be made with reacting ethylene oxide.The deficiency of this method is：Raw material is difficult to obtain, and grignard reaction, which is dealt with improperly, then can
Cause to burn, explode, security is poor, be not suitable for industrialized production.
（3）Using m-trifluoromethylbenzoic acid methyl esters as raw material（Chinese patent literature CN102112423A）, first with acetic acid first
Ester esterification obtains β keto esters, and then reselection hydrogenation obtains m-trifluoromethyl methyl phenylpropionate, finally in cupric oxide, oxidation
Catalytic hydrogenation is made in the presence of the mixed catalysts such as lanthanum, aluminum oxide, copper powder.The deficiency of this method is：Complex synthetic route,
Selective hydration and catalytic hydrogenation conditions are more harsh.
（4）Using m-trifluoromethyl benzenpropanoic acid as raw material, reduced through Lithium Aluminium Hydride（World patent document
WO2008058235A2）Or through borane reduction（Bioorganic ＆ Medicinal Chemistry, 23（13）, 3857-
3863）It is made.Former approach due to Lithium Aluminium Hydride meet water, make moist or improperly post-process all can easily cause burning, it is quick-fried
It is fried, security extreme difference, so as to be not suitable for industrialized production.Later approach because the toxicity of borine is big, easy spontaneous combustion characteristic,
It is also not suitable for industrialized production.
The content of the invention
It is an object of the invention to solve the above problems there is provided a kind of security it is higher, be suitable for industrialized large-scaled production between
The preparation method of trifluoromethyl phenylpropanol.
Realizing the technical scheme of the object of the invention is：A kind of preparation method of m-trifluoromethyl phenylpropanol, it is in inertia
In solvent, by reducing agent of boron hydride, lewis acid be co-catalyst, m-trifluoromethyl benzenpropanoic acid is reduced into a fluoroform
Base phenylpropanol.
Described reduction reaction temperature is 0~40 DEG C, preferably 20 DEG C.
The described reduction reaction time is 1~6h, preferably 3h.
Described atent solvent be methyl tertiary butyl ether(MTBE), isopropyl ether, methyltetrahydrofuran, tetrahydrofuran in one kind or
Two kinds.
The mol ratio of described boron hydride and m-trifluoromethyl benzenpropanoic acid is 1: 1~3: 1, preferably 2.5: 1.
Described boron hydride is sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride.
Described boron hydride is preferably to be added portionwise.
The mol ratio of described lewis acid and m-trifluoromethyl benzenpropanoic acid is 1: 1~2: 1, preferably 1: 1.
Described lewis acid be methanesulfonic acid, the concentrated sulfuric acid, trifluoroacetic acid, zinc chloride, alchlor or zirconium chloride, in order to
Reaction yield is further improved, described lewis acid is preferably methanesulfonic acid.
The good effect that the present invention has：（1）Method reaction condition of the invention is gentle, simple to operate, post processing is simple,
Especially security is higher, so as to be adapted to industrialized production.（2）When the method choice methanesulfonic acid of the present invention is Louis, also
With higher yield.
Embodiment
（Embodiment 1）
The preparation method of the m-trifluoromethyl phenylpropanol of the present embodiment is as follows：
54.5g m-trifluoromethyl benzenpropanoic acid is first added in four-hole boiling flask（0.25mol）With 270mL anhydrous tetrahydrochysene furan
Mutter, 2 DEG C ± 2 DEG C are cooled in ice-water bath；Then it is added portionwise under stirring（Temperature control is below 10 DEG C）23.8g hydroboration
Sodium（0.625mol）, add continuation and stir 10min；Then it is slowly added dropwise（Temperature control is below 10 DEG C）24.0g methanesulfonic acid
（0.25mol）, about 30min adds, and is finally to slowly warm up to room temperature（20℃±2℃）, 3h is reacted, control, which disappears, in sampling terminates anti-
Should.
After reaction terminates, 380mL water is added dropwise, stirs 30min, boils off tetrahydrofuran, add 190mL ethyl acetate, stir
Mix, point liquid, organic phase（Upper strata）With anhydrous sodium sulfate drying, concentration, vacuum distillation obtains trifluoro between 48.8g colourless oil liquids
Methyl phenylpropanol, yield is 95.1%, and purity is 99.4%（HPLC）.
（2~embodiment of embodiment 4）
Each embodiment is substantially the same manner as Example 1, and difference is shown in Table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| Lewis acid | Methanesulfonic acid 24.0g | Concentrated sulfuric acid 25.0g | Trifluoroacetic acid 28.5g | Anhydrous zinc chloride 34.0g |
| M-trifluoromethyl phenylpropanol | 48.8g | 46.8g | 46.0g | 47.0g |
| Yield | 95.1% | 90.8% | 89.5% | 91.3% |
| Purity | 99.4% | 98.9% | 99.2% | 99.1% |
Claims (8)
1. a kind of preparation method of m-trifluoromethyl phenylpropanol, it is characterised in that：It is in atent solvent, using boron hydride as
Reducing agent, lewis acid are co-catalyst, and m-trifluoromethyl benzenpropanoic acid is reduced into m-trifluoromethyl phenylpropanol；Described Louis
This acid is methanesulfonic acid.
2. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described reduction reaction
Temperature is 0~40 DEG C.
3. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described reduction reaction
Time is 1~6h.
4. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described atent solvent
For one or both of methyl tertiary butyl ether(MTBE), isopropyl ether, methyltetrahydrofuran, tetrahydrofuran.
5. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described boron hydride
Mol ratio with m-trifluoromethyl benzenpropanoic acid is 1: 1~3: 1.
6. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described boron hydride
For sodium borohydride, potassium borohydride, lithium borohydride or zinc borohydride.
7. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described boron hydride
To be added portionwise.
8. the preparation method of m-trifluoromethyl phenylpropanol according to claim 1, it is characterised in that：Described lewis acid
Mol ratio with m-trifluoromethyl benzenpropanoic acid is 1: 1~2: 1.
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| CN106496220B (en) * | 2016-10-21 | 2018-05-04 | 重庆乾泰生物医药有限公司 | A kind of preparation method of lysergol |
| CN106831324A (en) * | 2017-02-23 | 2017-06-13 | 四川什邡市三高生化实业有限公司 | A kind of preparation method of m-trifluoromethylphenyl propyl alcohol |
| CN107311844A (en) * | 2017-08-04 | 2017-11-03 | 六安佳诺生化科技有限公司 | The synthesis of m-trifluoromethyl phenylpropanol |
| CN108373405A (en) * | 2018-02-09 | 2018-08-07 | 连云港市国盛化工有限公司 | A kind of 2-（4- ethoxyl phenenyls）The preparation method of -2.2- dimethyl ethanols |
| CN108516922A (en) * | 2018-05-28 | 2018-09-11 | 杭州盛弗泰新材料科技有限公司 | A kind of preparation method of cyclopropyl-carbinol |
| CN110372746A (en) * | 2019-07-11 | 2019-10-25 | 辽宁石油化工大学 | A method of synthesis beta-amido phosphine oxide compound |
| CN113912620B (en) * | 2020-12-24 | 2022-09-13 | 常州市阳光药业有限公司 | Preparation method of 9, 9-bis (trifluoromethyl) -2,3,6, 7-xanthene tetracarboxylic dianhydride |
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| DE10117206A1 (en) * | 2001-04-06 | 2002-10-10 | Bayer Ag | Process for the preparation of halogen-substituted dibenzyl alcohols, these halogen-substituted dibenzyl alcohols and their use |
| JP2009073739A (en) * | 2007-09-19 | 2009-04-09 | Kaneka Corp | Method for producing highly pure optically active 1-aryl-1,3-propanediol acceptable as medicine intermediate |
| KR20110028647A (en) * | 2008-07-08 | 2011-03-21 | 인드-스위프트 래버러토리즈 리미티드 | Process for preparing cinacalcet and pharmaceutically acceptable salts thereof |
| CN103012066A (en) * | 2011-09-21 | 2013-04-03 | 北京理工大学 | Method for preparing 4,4'-bis(hydroxymethyl)biphenyl through reduction method |
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