CN102381990A - Preparation method of optically active N-benzyl phenylephrine - Google Patents
Preparation method of optically active N-benzyl phenylephrine Download PDFInfo
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- CN102381990A CN102381990A CN2010102702091A CN201010270209A CN102381990A CN 102381990 A CN102381990 A CN 102381990A CN 2010102702091 A CN2010102702091 A CN 2010102702091A CN 201010270209 A CN201010270209 A CN 201010270209A CN 102381990 A CN102381990 A CN 102381990A
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- asymmetric hydrogenation
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- DWMWFFWZJCCKCS-UHFFFAOYSA-N CN(CC(c1cc(O)ccc1)=O)Cc1ccccc1 Chemical compound CN(CC(c1cc(O)ccc1)=O)Cc1ccccc1 DWMWFFWZJCCKCS-UHFFFAOYSA-N 0.000 description 1
- JBBZPOHBHNEKIM-UHFFFAOYSA-N CN(CC(c1cc(O)ccc1)O)Cc1ccccc1 Chemical compound CN(CC(c1cc(O)ccc1)O)Cc1ccccc1 JBBZPOHBHNEKIM-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method of optically active N-benzyl phenylephrine, which is shown as a formula 1. The preparation method includes steps that due to alkali assistant and catalysis of chiral diphosphine- chiral diamine transition metal asymmetric hydrogenation catalyst, compound II and hydrogen realize asymmetric hydrogenation in liquor to complete a preparation process, wherein, '*' stands for chiral carbon, namely R or S configuration. The preparation method is high in product yield, higher in both chemical purity and optical purity, low in cost and simple in aftertreatment.
Description
Technical field
The present invention relates to the compound method of optically active N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine (N-benzyl neophryn).
Background technology
Neophryn has another name called phyenlephrinium, and the adrenomimetic drug medicine is used for diseases such as surgical operation prolongation toponarcosis time, nasal mucosa hyperemia, acute hypotension, infection toxic and anaphylactic shock.A large amount of demands is arranged clinically.
N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine (N-benzyl neophryn, compound I) is the important intermediate of synthetic neophryn.
According to prior art document EP 1147075,, carry out asymmetric reduction to N-benzyl-N-methyl-3-hydroxyl-α-methyl phenyl ketone amine in order to obtain optically active N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine.But the required rhodium catalyst price of this method is more expensive.The optical purity of products therefrom does not reach pharmaceutically the requirement to compound.In order to reach required optical purity, when finishing, reaction also need carry out loaded down with trivial details purification step, and cause yield to descend greatly.The hydrogenation ee value of EP1147075 report is 88%.For the ee value product brings up to 96%, need further purification step, product can lose about 30% like this.30% of this loss is otiose, handle or emit.This not only increases production cost, and gives the environment build-up of pressure, does not meet the synthetic developing direction with Chemical Manufacture of modern medicines.
Summary of the invention
Technical problem to be solved by this invention is among the preparation method for the intermediate N benzyl neophryn that overcomes existing synthetic neophryn; Defectives such as cost is higher, productive rate is low, optical purity is low and aftertreatment is loaded down with trivial details, and a kind of preparation method of new optically active N-benzyl neophryn is provided.Preparing method's product yield height of the present invention, chemical purity and optical purity are all higher, and cost is low, and aftertreatment is simple.
The present invention relates to a kind of suc as formula the optically active N-benzyl shown in the I-N-methyl-3-hydroxyl-methyl phenyl carbinol amine (N-benzyl neophryn; N-benzyl phyenlephrinium) preparation method; It comprises the following step: in the solvent, in the presence of alkaline assistant, under the catalysis of the chiral diphosphines shown in the formula IX-chiral diamine transition metal asymmetric hydrogenation catalyzer; Compound I I and hydrogen are carried out asymmetric hydrogenation, get final product;
(chiral phosphine ligand) MCl
2(Chiral Amine part)
IX
Wherein, " * " representes chiral carbon, i.e. R or S configuration; To be this area carry out the chirality phosphine commonly used-Chiral Amine transition metal ruthenium complex catalyst of asymmetric catalytic hydrogenation to carbonyl to catalyst I X, wherein:
M is transition metal ruthenium (Ru).
Chiral phosphine ligand is selected from chirality diphosphine ligand or its mirror image, and preferred chirality biaryl type diphosphine ligand or derivatives thereof (chiral atropoisomeric diphosphine derivatives) is like BINAP; MeOBIPHEP, P-Phos, Cn-TUNEPHOS; SEGPHOS, SYNPHOS, ClMeOBIPHEP; PHANPHOS or SDP, these all are the on record part in this area, and are as follows:
Wherein, Ar is phenyl or 3, the 5-dialkyl phenyl organic, shown in X:
Formula X
Wherein R is H, perhaps C
1～C
12Alkyl, preferred C
1～C
4Alkyl, most preferable.
Described Chiral Amine part be selected from optically active can chelating the chiral diamine of transition metal, preferred 1,2-phenylbenzene-1 or 1, two (4-the methoxyphenyl)-3-methyl isophthalic acids of 1-, 2-tetramethylenediamine.
Among the present invention, described catalyst I X can reach the best effect of asymmetric hydrogenation through the not phosphine part of isomorphism type and the suitable combination of amine ligand.
Among the present invention, described chiral phosphine ligand and described Chiral Amine part all exist R and S configuration.According to this area general knowledge, the selection of phosphine part configuration depends on the configuration of hydrogenated products.Can control the configuration of hydrogenated products through the configuration of selecting the phosphine part.
Among the present invention, the preferred asymmetric hydrogenation catalyzer of described catalyst I X Xyl-BINAP RuCl
2DAIPEN (CAS number is 220114-32-9) is when catalyst I X is Xyl-BINAP RuCl
2During DAIPEN, the absolute configuration of compound I is R.
Among the present invention, except that the kind of catalyzer, each condition of described preparation method all can be the condition of using always in the reaction of the carbonyl in the asymmetric hydrogenation simple ketone compound of this area, the preferred especially following condition of the present invention:
Described preferred solvents be water or organic solvent, wherein organic solvent is preferable is in ethers, aromatic hydrocarbons, halohydrocarbon and the alcohol one or more; Wherein said ethers is preferable is in ether, MTBE, DIPE, THF, methyltetrahydrofuran and the dioxane one or more; Described aromatic hydrocarbons is preferable is in benzene, toluene, chlorobenzene and the YLENE one or more; What described halohydrocarbon was preferable is methylene dichloride and/or ethylene dichloride; Described alcohol is preferable is in methyl alcohol, ethanol and the Virahol one or more.Said solvent is better is in water, methyl alcohol and the Virahol one or more, and better is Virahol.The volume mass of solvent and compound I I than preferable be 1～30ml/g.
Described alkaline assistant can be represented with formula M Y.Preferable, M is basic metal or earth alkali metal; Y is carbonate, hydroxide radical or C
1-C
12Alkoxyl group.The preferred K of described alkaline assistant
2CO
3, KOH, KOCH
3, KOCH (CH
3)
2, KOC (CH
3)
3, NaOH, NaOCH
3, NaOCH (CH
3)
2Or NaOC (CH
3)
3, more preferably KOH or KOC (CH
3)
3The consumption of alkaline assistant is preferable is 0.5～5 times of compound I I molar weight.
Among the present invention, the preferable form with hydrochloride of described compound I I is participated in reaction.
That the mol ratio of described asymmetric catalyst IX and compound I I is preferable is 1/50000-1/10, and that better is 1/20000-1/100, and that best is 1/5000-1/1000.
That the pressure of described hydrogen is preferable is 15-1500psi, and that better is 150-500psi.
The temperature of described asymmetric hydrogenation is preferable is-20-200 ℃, and better is 25-100 ℃.
Preferable complete with detection reaction of the time of described asymmetric hydrogenation, was generally 1～45 hour greater than till 99% like transformation efficiency.
Reaction of the present invention can be avoided loaded down with trivial details post-processing step after finishing, and only needs conventional neutralization, filtration, concentrates and can make chemical purity and all very high product of optical purity.
Among the preparation method of the present invention, above-mentioned each optimum condition can promptly get each preferred embodiments of the present invention in arbitrary combination under the prerequisite of this area general knowledge.
Except that specified otherwise, raw material that the present invention relates to and reagent are all commercially available to be got.
Among the present invention, the polarimetry purity of hydrogenated products I (with enantiomeric excess value, promptly the ee value is represented) can reach 95-99.9%.
Positive progressive effect of the present invention is:
The present invention utilizes low-cost ruthenium catalyst that N-benzyl-N-methyl-3-hydroxyl-α-methyl phenyl ketone amine is carried out asymmetric hydrogenation; Cost is lower, and aftertreatment is very simple, and reaction-ure conversion-age is high; Product yield, chemical purity and optical purity all higher; And reaction conditions is gentle, and is easy and simple to handle, is easy to industriallization.
Embodiment
Further specify the present invention with embodiment below, but the present invention is not limited.
Room temperature in following each instance is meant 15～35 ℃.
The preparation of embodiment 1 (R)-N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine
In the isopropanol suspension of the hydrochloride of N-benzyl 1-(3-hydroxy phenyl)-2-methylamino ethyl ketone (1.46 grams, 5.0 mmoles), stir and nitrogen atmosphere under add potassium tert.-butoxide (1.4 grams, 12.5 mmoles) and Xyl-BINAP RuCl
2DAIPEN (6.1 milligrams, 0.005 mmole).Said mixture is transferred in the autoclave pressure, feeds hydrogen to 30 crust, and reaction is 20 hours under the room temperature.The decompression back adds NH
4The Cl neutralization, the elimination solid, the gained clear liquid is with performing an analysis, and transformation efficiency is 99.6%, and the ee value is 95.6%.
The preparation of embodiment 2 (R)-N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine
In the isopropanol suspension of the hydrochloride of N-benzyl 1-(3-hydroxy phenyl)-2-methylamino ethyl ketone (1.46 grams, 5.0 mmoles), stir and nitrogen atmosphere under add potassium tert.-butoxide (1.23 grams, 11.0 mmoles) and Xyl-BINAP RuCl
2DAIPEN (3.0 milligrams, 0.002 mmole).Said mixture is transferred in the autoclave pressure, feeds hydrogen to 30 crust, and reaction is 20 hours under the room temperature.The decompression back adds NH
4The Cl neutralization, the elimination solid, the gained clear liquid is with performing an analysis, and transformation efficiency is 99.1%, and the ee value is 96.0%.
The preparation of embodiment 3 (R)-N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine
In the isopropanol suspension of the hydrochloride of N-benzyl 1-(3-hydroxy phenyl)-2-methylamino ethyl ketone (12.0 grams, 41.2 mmoles), stir and nitrogen atmosphere under add potassium tert.-butoxide (11.0 grams, 98.2 mmoles) and Xyl-BINAP RuCl
2DAIPEN (51.2 milligrams, 0.04 mmole).Said mixture is transferred in the autoclave pressure, feeds hydrogen to 30 crust, and reaction is 20 hours under the room temperature.Add after the decompression.NH
4Cl neutralization, elimination solid, gained clear liquid get 10.2 gram product, i.e. (R)-N-benzyl-N-methyl-3-hydroxyl-methyl phenyl carbinol amine behind the evaporate to dryness purifying.Product purity＞99.0%.Productive rate is 96.4%, and the ee value is 96.3%.
1H?NMR(DMSO-d
6，400MHz)δ2.20(s，3H)；2.40-2.43(m，1H)；2.49-2.54(m，2H)；3.55(s，2H)；4.62-4.65(m，1H)；4.90(s，br，1H)；6.60-6.62(dd，1H)；6.70-6.74(m，2H)；7.05-7.09(t，1H)；7.20-7.30(m，5H)；9.21(s，1H)。
Claims (13)
1. preparation method suc as formula the optically active N-benzyl neophryn shown in the I; It is characterized in that comprising the following step: in the solvent; In the presence of alkaline assistant; Under the catalysis of chiral diphosphines-chiral diamine transition metal asymmetric hydrogenation catalyzer, compound I I and hydrogen are carried out asymmetric hydrogenation, get final product;
(chiral phosphine ligand) MCl
2(Chiral Amine part)
IX
Wherein, " * " representes chiral carbon, i.e. R or S configuration; To be this area carry out the chirality phosphine commonly used-Chiral Amine transition metal complex catalyst of asymmetric catalytic hydrogenation to carbonyl to catalyst I X, and wherein: M is a ruthenium; Chiral phosphine ligand is selected from chirality diphosphine ligand or its mirror image, and described Chiral Amine part is selected from the chiral diamine of optically active ability chelating transition metal.
2. preparation method as claimed in claim 1 is characterized in that: described chirality diphosphine ligand is a chirality biaryl type diphosphine ligand or derivatives thereof; Described Chiral Amine part is 1,2-phenylbenzene-1 or 1, two (4-the methoxyphenyl)-3-methyl isophthalic acids of 1-, 2-tetramethylenediamine.
3. preparation method as claimed in claim 2 is characterized in that: described chirality diphosphine ligand is BINAP, MeOBIPHEP, P-Phos, Cn-TUNEPHOS, SEGPHOS, SYNPHOS, ClMeOBIPHEP, PHANPHOS or SDP, and structure is as follows:
Wherein, Ar is a phenyl or suc as formula 3 shown in the X, the 5-dialkyl phenyl organic:
Formula X
Wherein R is H or C
1～C
12Alkyl, preferred C
1～C
4Alkyl, most preferable.
4. like each described preparation method of claim 1～3, it is characterized in that: described chiral diphosphines-chiral diamine transition metal asymmetric hydrogenation catalyzer is Xyl-BINAP RuCl
2DAIPEN.
5. preparation method as claimed in claim 1 is characterized in that: described solvent is water or organic solvent, and wherein organic solvent is one or more in ethers, aromatic hydrocarbons, halohydrocarbon and the alcohol.
6. preparation method as claimed in claim 5 is characterized in that: described ethers is one or more in ether, MTBE, DIPE, THF, methyltetrahydrofuran and the dioxane; Described aromatic hydrocarbons is one or more in benzene, toluene, chlorobenzene and the YLENE; Described halohydrocarbon is methylene dichloride and/or ethylene dichloride; Described alcohol is one or more in methyl alcohol, ethanol and the Virahol.
7. preparation method as claimed in claim 5 is characterized in that: described solvent is one or more in water, methyl alcohol and the Virahol.
8. preparation method as claimed in claim 1 is characterized in that: described alkaline assistant representes that with formula M Y wherein, M is basic metal or earth alkali metal; Y is carbonate, hydroxide radical or C
1-C
12Alkoxyl group.
9. preparation method as claimed in claim 8 is characterized in that: described alkaline assistant is K
2CO
3, KOH, KOCH
3, KOCH (CH
3)
2, KOC (CH
3)
3, NaOH, NaOCH
3, NaOCH (CH
3)
2Or NaOC (CH
3)
3The consumption of alkaline assistant is 0.5～5 times of compound I I molar weight.
10. preparation method as claimed in claim 1 is characterized in that: the mol ratio of described asymmetric catalyst IX and compound I I is 1/50000-1/10.
11. preparation method as claimed in claim 10 is characterized in that: the mol ratio of described asymmetric catalyst IX and compound I I is 1/20000-1/100.
12. preparation method as claimed in claim 1 is characterized in that: the pressure of described hydrogen is 15-1500psi; Temperature-the 20-200 of described asymmetric hydrogenation ℃; The time of described asymmetric hydrogenation with detection reaction fully till.
13. preparation method as claimed in claim 12 is characterized in that: the pressure of described hydrogen is 150-500psi; The temperature of described asymmetric hydrogenation is 25-100 ℃.
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| CN2010102702091A CN102381990A (en) | 2010-08-31 | 2010-08-31 | Preparation method of optically active N-benzyl phenylephrine |
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| CN2010102702091A CN102381990A (en) | 2010-08-31 | 2010-08-31 | Preparation method of optically active N-benzyl phenylephrine |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103553942A (en) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | Preparation method of phenylephrine hydrochloride impurity |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0251164A2 (en) * | 1986-06-25 | 1988-01-07 | Kazuo Achiwa | New chiral phosphinopyrrolidine compounds and their use for asymetric synthesis of optically active compounds |
| US6187956B1 (en) * | 1999-01-21 | 2001-02-13 | Boehringer Ingelheim Pharma Kg | Method for preparing of L-phenylephrine hydrochloride |
| CN1680412A (en) * | 2005-01-27 | 2005-10-12 | 中国科学院上海有机化学研究所 | Transition metal complex, synthesis and use thereof |
| CN1884252A (en) * | 2006-06-02 | 2006-12-27 | 台州明翔化工有限公司 | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone |
| CN101037451A (en) * | 2005-01-27 | 2007-09-19 | 中国科学院上海有机化学研究所 | Transition metal complex, synthesizing method and application in catalytic hydrogenation reaction |
| CN101088984A (en) * | 2006-06-14 | 2007-12-19 | 台州明翔化工有限公司 | Process of synthesizing alpha-(N-methyl-N-benzylamin)-3-hydroxy acetophenone hydrochloride |
| CN101323630A (en) * | 2008-07-25 | 2008-12-17 | 中国科学院上海有机化学研究所 | Transient metal complex compound, synthetic method and use thereof |
-
2010
- 2010-08-31 CN CN2010102702091A patent/CN102381990A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0251164A2 (en) * | 1986-06-25 | 1988-01-07 | Kazuo Achiwa | New chiral phosphinopyrrolidine compounds and their use for asymetric synthesis of optically active compounds |
| US6187956B1 (en) * | 1999-01-21 | 2001-02-13 | Boehringer Ingelheim Pharma Kg | Method for preparing of L-phenylephrine hydrochloride |
| CN1680412A (en) * | 2005-01-27 | 2005-10-12 | 中国科学院上海有机化学研究所 | Transition metal complex, synthesis and use thereof |
| CN101037451A (en) * | 2005-01-27 | 2007-09-19 | 中国科学院上海有机化学研究所 | Transition metal complex, synthesizing method and application in catalytic hydrogenation reaction |
| CN1884252A (en) * | 2006-06-02 | 2006-12-27 | 台州明翔化工有限公司 | Process for synthesizing alpha-(N-methyl-benzyl)-3-hydroxy acetophenone |
| CN101088984A (en) * | 2006-06-14 | 2007-12-19 | 台州明翔化工有限公司 | Process of synthesizing alpha-(N-methyl-N-benzylamin)-3-hydroxy acetophenone hydrochloride |
| CN101323630A (en) * | 2008-07-25 | 2008-12-17 | 中国科学院上海有机化学研究所 | Transient metal complex compound, synthetic method and use thereof |
Non-Patent Citations (1)
| Title |
|---|
| JIAN-HUA XIE等: "Synthesis of Spiro Diphosphines and Their Application in Asymmetric Hydrogenation of Ketones", 《JOURNAL OF AMERICAN CHEMICAL SOCIETY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103553942A (en) * | 2013-11-13 | 2014-02-05 | 武汉武药科技有限公司 | Preparation method of phenylephrine hydrochloride impurity |
| CN103553942B (en) * | 2013-11-13 | 2015-11-18 | 武汉武药科技有限公司 | A kind of preparation method of phenylephrine hydrochloride impurity |
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Application publication date: 20120321 |