CN107868077A - A kind of synthetic method of (S) 3 methylamino 1 (base of thiophene 2) propyl alcohol - Google Patents
A kind of synthetic method of (S) 3 methylamino 1 (base of thiophene 2) propyl alcohol Download PDFInfo
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- CN107868077A CN107868077A CN201711179854.0A CN201711179854A CN107868077A CN 107868077 A CN107868077 A CN 107868077A CN 201711179854 A CN201711179854 A CN 201711179854A CN 107868077 A CN107868077 A CN 107868077A
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- thiophene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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Abstract
The invention discloses a kind of synthetic method of (S) 3 methylamino 1 (base of thiophene 2) propyl alcohol, it is characterised in that comprises the following steps：In the environment of alkali and solvent, using 3 methylamino 1 (base of thiophene 2) acetone as raw material, under transition metal complex catalyst effect, carry out catalytic hydrogenation reaction, generate (S) 3 methylamino 1 (base of thiophene 2) propyl alcohol, the method of the present invention is only the product that can obtain high-purity with a step catalytic hydrogenation reaction, greatly shorten process cycle, catalyst amount is few, production cost is low, and reaction condition is gentle and process stabilizing, high conversion rate, it is few to react generation environment pollution, beneficial to realizing industrialized production.
Description
Technical field
The invention belongs to pharmaceutical-chemical intermediate to synthesize field, relate generally to a kind of (S) -3- methylaminos -1- (thiophene -
2- yls) propyl alcohol synthetic method.
Background technology
Duloxetine (Duloxetine), entitled (γ S)-N- methyl-γ-(1- the naphthoxys) -2- thiophenepropyIamines of chemistry, it is
By the serotonin (5-HT) and norepinephrine (NE) dual reuptake depression of the research and development of Eli Lilly companies of the U.S., face
Bed hydrochloride, trade name Cymbalta, its structural formula are as follows：
Compared with other western spit of fland class medicines, this product is safe and effective, side effect, and the other symptoms of depression, such as whole body are ached
Pain and gastrointestinal disturbance are also effective in cure, and the III clinical trial phases for treating the tonicity urinary incontinence are also completed, and have very high
Market value.Its synthetic route is：
Chiral intermediate 1 is the key for synthesizing Duloxetine it can be seen from the synthetic method of Duloxetine, its optics
Purity directly affects the product quality of Duloxetine.
The synthetic method of the intermediate 1 of present Duloxetine has following several：
Method one：With the cyano group alcohol of racemization the ester of chirality, then degree of the obtaining Lip river after reductive hydrolysis are obtained through lipase hydrolysis
Western spit of fland chiral intermediate 1, such a method and step length, yield is low, also to use substantial amounts of enzyme and be reacted.
Method two：Chiral asymmetric reduction is carried out using the thienone of chloro, obtains chiral alcohol, then methylamine obtains again
Chiral intermediate 1, such a method yield are formed in the first step, and atom utilization is poor, causes cost height.
The content of the invention
The problem of existing for prior art, it is an object of the invention to provide a kind of efficiency high, cost is low, good product quality
Synthesis (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol method.
For achieving the above object, this invention takes following technical scheme：
Zhongshan Enantiotech Corporation Ltd. is PCT/CN2012/081037, international publication number in international application no
It is new containing phosphine, nitrogen ligand metal ruthenium complex that one kind is disclosed in international monopoly for the A1 of WO 2014/036702, passes through change
With NH2The dinitrogen part of-N (sp2) architectural feature, the hydrogenation generation phase of aryl ketones can be catalyzed efficient, high enantioselectivity
The chiral alcohol answered.The present invention uses the metal ruthenium complex to carry out catalytic hydrogenation reaction as catalyst and prepares (S) -3- methyl ammonia
Base -1- (thiophene -2- bases) propyl alcohol.Concrete scheme is as follows：
The method of one kind synthesis (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol, comprises the following steps：
In the environment of alkali and solvent, using 3- methylaminos -1- (thiophene -2- bases), acetone is raw material, in transition metal network
Under mixture catalyst effect, catalytic hydrogenation reaction is carried out, generates (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol.
Preferably, the formula of the transition metal complex catalyst is MLnL ' XY, wherein, M Ru, wherein X and Y phases
With or it is different, X is chlorine, bromine, iodine or hydrogen, and Y is chlorine, bromine, iodine or BH4, and L, L ' are R configurations, S configurations or raceme, n=1 or
2；
As n=1, L BINAP, MeO-BIPHEP, DIOP or SegPhos；
As n=2, L is P (C6H5) 3 or P (C6H4-4-CH3) 3；L ' be DPEN, DAIPEN, 1,2- cyclohexanediamine or
L ' has the structure of formula III：
In formula III, Z is NH or O；R1, R2It is the alkyl of hydrogen or 1~12 carbon atom, the alkyl of 1~12 carbon atom
Selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl
Base, alkyl-substituted benzyl, whenFor cyclic hydrocarbon radical when, be propylidene or butylidene.
It is further preferred that the transition metal complex catalyst is selected from IV~VII structure：
When transition metal complex catalyst is in IV~VII structure, (S) -3- methylaminos -1- for being prepared
The structure of (thiophene -2- bases) propyl alcohol is R configurations (II), and the reaction equation is：
It is further preferred that the transition metal complex catalyst is selected from Ⅸ~Ⅻ structure：
When transition metal complex is in Ⅸ~Ⅻ structure, (S) -3- methylaminos -1- for being prepared (thiophene -
2- yls) structure of propyl alcohol is S configurations (III), the reaction equation is：
Preferably, the mol ratio of 3, the 5- bis trifluoromethyls acetophenone and transition metal complex be 20000~
1000000：1.
Preferably, during the course of the reaction, the concentration of the alkali is 5~200mmol/L.
Preferably, the alkali be potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, pyridine, triethylamine, diethylamine, 1,
2- ethylenediamines or alkoxy base.
It is further preferred that the alkoxy base is potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, 2,2,4-3- methyl-penta
Alkoxy potassium, 2,2,4-3- methyl-pentane epoxide sodium or 2,2,4-3- methyl-pentane epoxide lithiums.
Preferably, the solvent is non-protonic solvent or the mixed solvent of protonic solvent and non-protonic solvent.Its
Described in non-protonic solvent be dichloromethane, toluene, tetrahydrofuran, methyl tertiary butyl ether(MTBE) or methyl-isobutyl ether, the matter
Sub- property solvent is methanol, ethanol, isopropanol or the tert-butyl alcohol.The in the mixed solvent, the protonic solvent and aprotic are molten
The volume ratio of agent is 1:10~10:1.
Preferably, the reaction pressure of the catalytic hydrogenation reaction is 0.5MPa~10Mpa.
Preferably, the reaction temperature of the catalytic hydrogenation reaction is 25~100 DEG C, and the reaction time is 4~24 hours.
Beneficial effects of the present invention：
The present invention is using 3- methylaminos -1- (thiophene -2- bases) acetone as raw material, using a kind of new containing phosphine, nitrogen ligand gold
Category ruthenium complex carries out catalytic hydrogenation reaction as catalyst and 3- methylaminos -1- (thiophene -2- bases) propyl alcohol is prepared.With mesh
The synthesis technique of the industrialization of preceding report is compared, and the synthetic method route only can obtain high-purity with a step catalytic hydrogenation reaction
Product, greatly shorten process cycle, catalyst amount is few, and production cost is low, and reaction condition is gentle and process stabilizing, conversion ratio
Height, reaction generation environment pollution is few, beneficial to realizing industrialized production.
Embodiment
In order to preferably explain the present invention, it is described further in conjunction with specific examples below, but the present invention is unlimited
In specific embodiment.
Embodiment 1
Transition metal complex catalyst uses structure I V, the transition metal complex compound catalyst for [RuCl2 ((R,
R)-DIOP){(1H-benzo[d]imidazol-2-yl)ethanamine}]；Alkali uses potassium tert-butoxide；Solvent uses toluene.
The mol ratio of reaction raw materials 3- methylaminos -1- (thiophene -2- bases) acetone (I) and transition metal complex is 30000.Above-mentioned original
The dosage of material is shown in Table 1.
In 100L stainless steel autoclaves, 3- methylaminos -1- (thiophene -2- bases) acetone, toluene are added, in N2 atmosphere
Under, add catalyst [RuCl2((S, S)-DIOP) { (1H-benzo [d] imidazol-2-yl) ethanamine }] and tertiary fourth
Potassium alcoholate；After replacing hydrogen, H is filled2To 5atm, 100 DEG C of stirring reactions, when Hydrogen Vapor Pressure is invariable (about 4 hours), stop stirring
Mix, by the H in reactor2Emptying, to reaction solution sample, carry out conventional post processing (filtering, centrifugation, washing, liquid separation, concentration,
The operation such as dry), solid product is obtained, passes through the detection that chiral column carries out product yield and ee values, the absolute configuration of product
S configurations are defined as by polarimeter, the conversion ratio 99.5% of product, enantiomeric excess value 98%, absolute configuration is S configurations.
The supplementary material of the embodiment 1 of table 1 and dosage list
Embodiment 2
Transition metal complex catalyst uses structure I V, the transition metal complex compound catalyst for [RuCl2 ((R,
R)-DIOP){(1H-benzo[d]imidazol-2-yl)ethanamine}]；Alkali uses potassium tert-butoxide；Solvent using toluene and
Isopropanol is 3 by volume:1 mixed solvent.Reaction raw materials 3- methylaminos -1- (thiophene -2- bases) acetone (I) and transition gold
The mol ratio for belonging to complex compound is 30000.The dosage of above-mentioned raw materials is shown in Table 2.
In 100L stainless steel autoclaves, 3- methylaminos -1- (thiophene -2- bases) acetone, toluene, isopropanol are added,
Under n 2 atmosphere, catalyst [RuCl is added2((S,S)-DIOP){(1H-benzo[d]imidazol-2-yl)
Ethanamine }] and potassium tert-butoxide；After replacing hydrogen, H is filled2To 5atm, 100 DEG C of stirring reactions, when Hydrogen Vapor Pressure is invariable
When (about 4 hours), stop stirring, by the H in reactor2Emptying, to reaction solution sample, carry out conventional post processing (filtering, from
The heart, washing, liquid separation, concentration, drying etc. operate), solid product is obtained, the inspection of product yield and ee values is carried out by chiral column
To survey, the absolute configuration of product is defined as S configurations by polarimeter, the conversion ratio 99.7% of product, enantiomeric excess value 98.2%,
Absolute configuration is S configurations.
The supplementary material of the embodiment 2 of table 2 and dosage list
The specific embodiment of the present invention is the foregoing is only, is not intended to limit the scope of the invention, every utilization
The equivalent transformation that the present invention makees, or other related technical fields are directly or indirectly used in, similarly it is included in the present invention's
Among scope of patent protection.
Claims (10)
1. a kind of synthetic method of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol, it is characterised in that comprise the following steps：
In the environment of alkali and solvent, using 3- methylaminos -1- (thiophene -2- bases), acetone is raw material, in transition metal complex
Under catalyst action, catalytic hydrogenation reaction is carried out, generates (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol.
2. the synthetic method of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to claim 1, its feature exist
In, the formula of the transition metal complex catalyst is MLnL ' XY, wherein, M Ru, wherein X are identical or different with Y, X
For chlorine, bromine, iodine or hydrogen, Y is chlorine, bromine, iodine or BH4, and L, L ' are R configurations, S configurations or raceme, n=1 or 2；
As n=1, L BINAP, MeO-BIPHEP, DIOP or SegPhos；
As n=2, L is P (C6H5)3Or P (C6H4-4-CH3)3；
L ' is that DPEN, DAIPEN, 1,2- cyclohexanediamine or L ' have the structure of formula III：
In formula III, Z is NH or O；R1, R2It is the alkyl of hydrogen or 1~12 carbon atom, the alkyl of 1~12 carbon atom is selected from
Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, normal-butyl, the tert-butyl group, cyclopenta, cyclohexyl, suberyl, phenyl, benzyl,
Alkyl-substituted benzyl, whenFor cyclic hydrocarbon radical when, be propylidene or butylidene.
3. the synthetic method of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to claim 2, its feature exist
In the transition metal complex catalyst is selected from IV~VII structure：
The structure of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol being prepared is R configurations.
4. the synthetic method of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to claim 2, its feature exist
In the transition metal complex catalyst is selected from IV~VII structure：
The structure of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol being prepared is S configurations.
5. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that the mol ratio of 3, the 5- bis trifluoromethyls acetophenone and transition metal complex be 20000~
1000000：1.
6. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that during the course of the reaction, the concentration of the alkali is 5~200mmol/L.
7. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that the alkali is potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, pyridine, triethylamine, diethylamine, 1,2-
Ethylenediamine or alkoxy base.
8. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that the solvent is non-protonic solvent or the mixed solvent of protonic solvent and non-protonic solvent.
9. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that the reaction pressure of the catalytic hydrogenation reaction is 0.5MPa~10Mpa.
10. the synthesis side of (S) -3- methylaminos -1- (thiophene -2- bases) propyl alcohol according to any one of claim 1-4
Method, it is characterised in that the reaction temperature of the catalytic hydrogenation reaction is 25~100 DEG C, and the reaction time is 4~24 hours.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000606A (en) * | 2010-10-12 | 2011-04-06 | 中国科学院兰州化学物理研究所 | Chiral ruthenium catalyst and use thereof in asymmetric hydrogenation of ketone |
| WO2011135753A1 (en) * | 2010-04-28 | 2011-11-03 | Takasago International Corporation | Ruthenium complex and method for preparing optically active alcohol compound |
| WO2014036702A1 (en) * | 2012-09-06 | 2014-03-13 | 中山奕安泰医药科技有限公司 | New metal ruthenium complex having nitrogen ligand, preparation method therefor, and uses thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011135753A1 (en) * | 2010-04-28 | 2011-11-03 | Takasago International Corporation | Ruthenium complex and method for preparing optically active alcohol compound |
| CN102000606A (en) * | 2010-10-12 | 2011-04-06 | 中国科学院兰州化学物理研究所 | Chiral ruthenium catalyst and use thereof in asymmetric hydrogenation of ketone |
| WO2014036702A1 (en) * | 2012-09-06 | 2014-03-13 | 中山奕安泰医药科技有限公司 | New metal ruthenium complex having nitrogen ligand, preparation method therefor, and uses thereof |
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Application publication date: 20180403 |