阅读说明：本技术 一种地诺帕明及其中间体的制备方法 (Preparation method of dienopamine and intermediate thereof ) 是由 马保德 邵攀霖 吴超 王江 张绪穆 于 2019-09-23 设计创作，主要内容包括：本发明公开了一种地诺帕明及其中间体的制备方法,具体为通过Ir/f-amphox催化不对称氢化制备地诺帕明的方法。该方法步骤简单,操作简便,条件温和,可以高效不对称氢化合成地诺帕明,催化剂用量可以仅为0.002mol％(S/C＝50,000),具有巨大的工业应用价值。(The invention discloses a preparation method of dienopamine and an intermediate thereof, in particular to a method for preparing dienopamine by Ir/f-amphox catalytic asymmetric hydrogenation. The method has simple steps, simple and convenient operation and mild conditions, can synthesize the dienopamine by high-efficiency asymmetric hydrogenation, can only use 0.002 mol% (S/C is 50,000) of the catalyst, and has huge industrial application value.)

1. The preparation method of the dienopamine intermediate IV is characterized by comprising the following steps:

the 2-bromo-4' -hydroxyacetophenone II and 3, 4-dimethoxyphenethylamine III are subjected to two-step reaction in a solvent to prepare a dienopamine intermediate alpha-aminoketone IV.

。

2. The method for preparing the dienopamine I by catalytic asymmetric hydrogenation is characterized in that:

under the atmosphere of hydrogen, in a protonic organic solvent, in the presence of a catalyst obtained by complexing chiral ligand f-amphox and metal iridium salt, adding a dienopamine intermediate alpha-aminoketone IV and alkali to perform asymmetric hydrogenation reaction to obtain dienopamine I:

the chiral ligand f-amphox is a compound represented by the following general formula L:

in the general formula L, R represents methyl, isopropyl, tert-butyl, phenyl, benzyl or other arbitrary C₁-C₆A linear or branched or cyclic substituent of (a); ar represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dimethyl-4-methoxyphenyl, 3,4, 5-trimethylphenyl, 3, 5-di-tert-butylphenyl, 3, 5-di-tert-butyl-4-methoxy and 3, 5-di-tert-butyl-4-methyl.

3. The preparation method of claim 1, wherein the molar ratio of the 2-bromo-4' -hydroxyacetophenone II to the 3, 4-dimethoxyphenethylamine III is 1: 1.9-2.2.

4. The method according to claim 1, wherein the solvent is acetonitrile.

5. The method according to claim 2, wherein the asymmetric hydrogenation is carried out at a reaction temperature of 30 to 70 ℃ under a hydrogen pressure of 20 to 60 atm for 6 to 120 hours.

6. The process of claim 2, wherein the catalyst is prepared from a chiral ligand f-amphox and a metal iridium saltⁱComplexing in PrOH; the molar ratio of the metal iridium salt to the chiral ligand f-amphox is 0.5:1.0-1.2, the temperature of the complex reaction is room temperature, and the time of the complex reaction is 1-3 hours.

7. The process according to claim 6, wherein the catalyst obtained by the complexation is used directly for catalyzing the asymmetric hydrogenation without separation.

8. The process of any of claims 2 to 6, wherein the metal iridium salt is [ Ir (COD) Cl]₂。

9. The method of claim 2, wherein the molar ratio of the base to the dienopamine intermediate alpha-aminoketone IV is 2.0-2.4: 1.

10. The method of claim 2 or 9, wherein the base comprises: one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, triethylamine, and N, N-diisopropylethylamine.

Technical Field

The invention belongs to the field of medicinal chemical synthesis, and particularly relates to a preparation method of dienopamine and an intermediate thereof.

Background

Dinopamine (Denopamine), chemical name: (R- [ [ [2- (3, 4-dimethoxyphenyl) ethyl ] amino ] methyl ] -4-hydroxybenzyl alcohol, CAS: 71771-90-9, molecular formula: C18H23ClNO4, molecular weight: 317.383, structural formula:

dienopamine [ trade name: kalgut (カ ル グ ー ト) ] was developed by Tanabe Seiyaku, co., Ltd, mitd, mitsubishi drug corporation, japan, first introduced in japan in 1988. The compound is an oral cardiotonic (5mg or 10mg tablet or 5% granule) that selectively stimulates adrenergic beta 1-receptor to provide sustained enhancement of myocardial contractility, but has little or no stimulation of beta 2-and alpha-receptors, thus not affecting heart beat number, and is useful for treating angina pectoris, and may also have potential uses for treating congestive heart failure and clearing pulmonary edema.

Disclosure of Invention

In one aspect, the invention provides a dienopamine key intermediate alpha-aminoketone and a method for synthesizing dienopamine through Ir/f-amphox catalytic asymmetric hydrogenation, which at least solve some problems mentioned in the background technology.

The invention is realized by the following technical scheme.

Preparation of nopamine key intermediate alpha-aminoketone IV:

the first step of reaction: after the reaction of 3, 4-dimethoxy phenethylamine III and 2-bromo-4' -hydroxyacetophenone II in acetonitrile is finished, filtering to remove solids, and concentrating the filtrate; the solid can directly continue to react with the 2-bromo-4' -hydroxyacetophenone II in the first step after being dissociated by alkali. The second step of reaction: and dissolving the filtrate in acetone again, introducing excessive hydrogen chloride gas, filtering, washing a filter cake by using acetone to obtain a pure white solid, and drying in vacuum to obtain the dienopamine key intermediate alpha-aminoketone IV.

The molar ratio of the 3, 4-dimethoxy phenethylamine III to the 2-bromo-4' -hydroxyacetophenone II is 1.90-2.2: 1.

Process for the synthesis of dienopamine by Ir/f-amphox catalyzed asymmetric hydrogenation:

in the presence of a catalyst obtained by complexing a chiral ligand f-amphox (L) and a metal iridium salt in a protic organic solvent under the hydrogen atmosphere, adding a key intermediate alpha-aminoketone IV and an alkali to perform an asymmetric hydrogenation reaction to obtain dienopamine I;

the chiral ligand f-amphox is a compound represented by the following general formula L:

in the general formula L, R represents methyl, isopropyl, tert-butyl, phenyl, benzyl or other arbitrary C₁-C₆A linear, branched or cyclic substituent of (a); ar represents phenyl, 4-methylphenyl, 4-methoxyphenyl, 3, 5-dimethylphenyl, 3, 5-dimethyl-4-methoxyphenyl, 3,4, 5-trimethylphenyl, 3, 5-di-tert-butylphenyl, 3, 5-di-tert-butyl-4-methoxy and 3, 5-di-tert-butyl-4-methyl.

When the dienopamine intermediate alpha-aminoketone IV is subjected to asymmetric hydrogenation reaction, the reaction temperature is 30-70 ℃, the hydrogen pressure is 20-60 atmospheric pressure, and the reaction time is 6-120 hours

The catalyst is prepared from chiral ligand f-amphox (L) and metal iridium saltⁱComplexing in PrOH. The molar ratio of the metal iridium salt to the chiral ligand is 0.5:1.0-1.2, the reaction temperature is room temperature, and the reaction time is 1-3 hours. The preferred metal iridium salt in the present invention is [ Ir (COD) Cl]₂。

The catalyst obtained by complexing is not separated and is directly used for catalyzing asymmetric hydrogenation reaction in the presence of alkali.

The molar ratio of the alkali to the dienopamine intermediate alpha-aminoketone IV is 2.0-2.4: 1.

The molar ratio of the catalyst to the dienopamine intermediate alpha-aminoketone IV is 1: 1000-50000, preferably 1: 30000-50000.

One of the above technical solutions has the following advantages or beneficial effects:

in conclusion, the tridentate ligand catalyst system Ir/f-amphox is adopted, and due to high stability and reaction activity of the tridentate ligand catalyst system Ir/f-amphox, the inactivation caused by coordination of a product to a catalyst metal center is overcome. Compared with the prior art, the process is more advanced. Especially in the chiral generation step, the technology of the invention can obtain the enantioselectivity of more than 99 percent and the catalyst conversion number (TON) of 50,000, which is far higher than all known reports at present. Meanwhile, compared with the prior art, the method has the advantages of simple and convenient process operation, obviously reduced intermediate products and three wastes, and suitability for industrial scale-up production.

In addition, the method has the characteristics of simple operation, low cost, extremely high conversion rate and selectivity, high atom economy and environmental friendliness, and extremely high industrial value.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

When the method is used for preparing the dienopamine key intermediate alpha-aminoketone IV, the solvent used in the first step of reaction is preferably acetonitrile, acetone, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether and the like, and is further preferably acetonitrile; the solvent used in the second reaction step is preferably ethanol, acetonitrile, acetone, tetrahydrofuran, methyl t-butyl ether or the like, and more preferably acetone.

The method is an asymmetric hydrogenation reaction of a dienopamine intermediate alpha-aminoketone IV in the presence of a chiral catalyst, the catalyst is formed by matching metal iridium salt with a chiral ligand f-amphox, and the ligand structure is shown as a general formula L.

The preferable metal iridium salt in the present invention is [ Ir (COD) Cl]₂Wherein the dimer is 1,5-cyclooctadiene iridium chloride dimer, and the dimer is Chloro (1,5-cyclooctadiene) iridium (I) dimer.

In the invention, chiral ligand and metal iridium salt are inⁱWhen the target catalyst is obtained by the reaction in PrOH, the molar ratio of the metal iridium salt to the chiral ligand is 0.5:1.0-1.2, preferably 0.5: 1.0-1.1, and more preferably 0.5: 1.05.

In the invention, when the chiral ligand and the metal iridium salt react in the solvent to obtain the target catalyst, the reaction temperature can be set according to needs, preferably 30-70 ℃, and more preferably 55-60 ℃.

In the present invention, the pressure of the reaction hydrogen is 30 to 60 atm, preferably 30 to 50 atm, and more preferably 40 to 45 atm.

In the present invention, the base includes: one or more of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium methoxide, sodium methoxide, potassium methoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and cesium carbonate. Preferably, sodium tert-butoxide or potassium tert-butoxide is used, and sodium tert-butoxide is more preferred.

In the present invention, the molar ratio of the α -aminoketone IV to the base is 1:2.0 to 2.4, preferably 1:2.15 to 2.25, and more preferably 1: 2.2.

In the present invention, the alpha-aminoketone IV is reacted withⁱThe molar concentration of PrOH is 0.2-2.5, preferably 1.5-2.25, and more preferably 2.0-2.1.

In the present invention, when the α -aminoketone IV is subjected to asymmetric hydrogenation, the molar ratio of the α -aminoketone IV to the catalyst is 1000 to 50000: 1, preferably 1: 20000-. At this time, there is practically no limitation on the molar ratio of the α -aminoketone to the in-situ catalyst, because the high catalytic efficiency of the in-situ catalyst enables the asymmetric hydrogenation of the ketone to proceed smoothly even with a small amount of the in-situ catalyst, and a high conversion rate and induction effect can be obtained.