阅读说明：本技术 R-1-(萘-1-基）乙醇的制备方法 (Preparation method of R-1- (naphthalene-1-yl) ethanol ) 是由 李彦雄 蒙发明 于永海 黄承焕 黄晋 王妙红 于 2020-06-09 设计创作，主要内容包括：本发明涉及一种R-1-(萘-1-基)乙醇的制备方法,其步骤包括：1-萘乙酮在催化剂的催化下进行不对称氢化反应；所述催化剂具有如下式(I)所示结构特征。该制备方法制备得到R-1-(萘-1-基)乙醇产品手性纯度更高,同时保证较高的转化率,反应可以在更低的压力条件下进行反应,便于大规模生产应用,且采用的催化剂能够回收利用,避免重金属污染,降低成本。<Image he="388" wi="456" file="DDA0002530651760000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a preparation method of R-1- (naphthalene-1-yl) ethanol, which comprises the following steps: carrying out asymmetric hydrogenation reaction on the 1-acetophenone under the catalysis of a catalyst; the catalyst has the structural characteristics shown in the following formula (I). The R-1- (naphthalene-1-yl) ethanol product prepared by the preparation method has higher chiral purity, higher conversion rate is ensured, the reaction can be carried out under lower pressure, large-scale production and application are facilitated, and the adopted catalyst can be recycled, so that heavy metal pollution is avoided, and the cost is reduced.)

1. A preparation method of R-1- (naphthalene-1-yl) ethanol is characterized in that the reaction formula is as follows:

the method comprises the following steps: carrying out asymmetric hydrogenation reaction on the 1-acetophenone under the catalysis of a catalyst;

the catalyst has the structural characteristics shown as the following formula (I):

wherein the content of the first and second substances,represents a bisphosphine ligand;

x is selected from-Cl, -Br, -I or-H; y is selected from-Cl, -Br or-I;

r is selected from-H or C1-C12 alkyl.

2. The method for producing R-1- (naphthalen-1-yl) ethanol according to claim 1, wherein the polymerization degree of PEG in the formula (I) is 400 to 2000.

3. The method for producing R-1- (naphthalen-1-yl) ethanol according to claim 2, wherein the polymerization degree of PEG in the formula (I) is 800 to 1200.

4. The method for producing R-1- (naphthalen-1-yl) ethanol according to any one of claims 1 to 3, wherein the asymmetric hydrogenation comprises the steps of:

dissolving the 1-acetonaphthone by a solvent, adding alkali and the catalyst, and introducing hydrogen for reaction.

5. The method for producing R-1- (naphthalen-1-yl) ethanol according to claim 4, wherein the hydrogen is introduced so that the reaction is carried out under a pressure of 0 to 7 atm.

6. The method for producing R-1- (naphthalen-1-yl) ethanol according to claim 5, wherein the hydrogen gas is introduced so that the reaction is carried out under a pressure of 2 to 5 atm.

7. The method for producing R-1- (naphthalen-1-yl) ethanol according to claim 4, wherein the reaction temperature is 35 to 45 ℃.

8. The process for producing R-1- (naphthalen-1-yl) ethanol according to claim 4, wherein the base is selected from at least one of potassium tert-butoxide, potassium ethoxide and sodium ethoxide; and/or the presence of a catalyst in the reaction mixture,

the solvent is selected from at least one of ethanol, methanol, isopropanol, toluene and dichloromethane.

9. A method for synthesizing R-1- (naphthalene-1-yl) ethylamine is characterized by comprising the following steps:

synthesizing R-1- (naphthalen-1-yl) ethanol according to the synthesis method of any one of claims 1 to 8;

and (3) sulfonylating and aminolysis are carried out on the R-1- (naphthalene-1-yl) ethanol.

10. A synthetic method of cinacalcet is characterized by comprising the following steps: r-1- (naphthalen-1-yl) ethylamine was synthesized using the synthesis method described in claim 9.

Technical Field

The invention relates to compound synthesis, in particular to a preparation method of R-1- (naphthalene-1-yl) ethanol.

Background

Cinacalcet, chemical name N- [ (1R) -1- (1-naphthyl) ethyl ] -3- (3- (trifluoromethyl) phenyl) propan-1-amine, structure of which is shown as following formula (1). Cinacalcet, the first drug in a new class of compounds called calcimimetics (calcimetics), activates the calcium receptor in the parathyroid gland, thereby reducing parathyroid hormone (PTH) secretion, thereby effectively delaying the progression of cardiovascular calcification, reducing the incidence of cardiovascular events, and improving all-cause mortality. Meanwhile, cinacalcet can also effectively reduce the product of PTH, calcium, phosphorus, calcium and phosphorus of SHPT dialysis patients, reduce the bone formation rate and improve bone diseases.

The formula is shown in a structural formula (1), the cinacalcet has a chiral center, the chiral center is generally constructed by an important intermediate R-1- (naphthalene-1-yl) ethylamine, and the structure of the R-1- (naphthalene-1-yl) ethylamine is shown in a formula (2):

the traditional preparation method generally uses the corresponding racemate as a raw material, and adopts tartaric acid and other resolving agents for separation, so that the yield is low, and the material waste is large. In another method, 1-acetonaphthone is used as a raw material and passes through a chiral catalyst (S, S) -Diop-RuCl₂Carrying out asymmetric catalytic reduction on- (S) -Me-BIMA, and carrying out sulfonylation and aminolysis on the obtained R-configuration alcohol (R-1- (naphthalene-1-yl) ethanol) to obtain the intermediate. However, this method needs to be carried out under higher pressure conditions, and is not free from a challenge for scale-up production. Meanwhile, the chiral purity of cinacalcet serving as a medicine is closely related to the medicine effect, and the chiral purity (ee value is 94-98%) of the R-configuration alcohol prepared by the method is further to be improvedAnd (5) rising.

Disclosure of Invention

Based on this, it is necessary to provide a process for producing R-1- (naphthalen-1-yl) ethanol. The R-1- (naphthalene-1-yl) ethanol product prepared by the preparation method has higher chiral purity, higher conversion rate is ensured, the reaction can be carried out under lower pressure, large-scale production and application are facilitated, and the adopted catalyst can be recycled, so that heavy metal pollution is avoided, and the cost is reduced.

The specific technical scheme is as follows:

a preparation method of R-1- (naphthalene-1-yl) ethanol has the following reaction formula:

carrying out asymmetric hydrogenation reaction on the 1-acetophenone under the catalysis of a catalyst;

the catalyst has the structural characteristics shown as the following formula (I):

wherein the content of the first and second substances,represents a bisphosphine ligand;

x is selected from-Cl, -Br, -I or-H; y is selected from-Cl, -Br or-I;

r is selected from-H or C1-C12 alkyl.

In one embodiment, the polymerization degree of PEG in the formula (I) is 400-2000.

In one embodiment, in the formula (I), the polymerization degree of PEG is 800-1200.

In one embodiment, the asymmetric hydrogenation reaction comprises the steps of:

dissolving the 1-acetonaphthone by a solvent, adding alkali and the catalyst, and introducing hydrogen for reaction.

In one embodiment, the hydrogen is introduced to carry out the reaction under the condition that the pressure is 0-7 atm.

In one embodiment, the hydrogen is introduced to carry out the reaction under the condition that the pressure is 2-5 atm.

In one embodiment, the reaction temperature is 35-45 ℃.

In one embodiment, the base is selected from at least one of potassium tert-butoxide, potassium ethoxide, and sodium ethoxide.

In one embodiment, the solvent is selected from at least one of ethanol, methanol, isopropanol, toluene, and dichloromethane.

The invention also provides a synthetic method of R-1- (naphthalene-1-yl) ethylamine, which comprises the following steps:

synthesizing R-1- (naphthalen-1-yl) ethanol according to the synthesis method of any one of claims 1 to 8;

and (3) sulfonylating and aminolysis are carried out on the R-1- (naphthalene-1-yl) ethanol.

The invention also provides a synthetic method of cinacalcet, which comprises the following steps: r-1- (naphthalen-1-yl) ethylamine was synthesized using the synthesis method described in claim 9.

Compared with the prior art, the invention has the following beneficial effects:

the invention provides a preparation method of R-1- (naphthalene-1-yl) ethanol, which adopts a proper catalyst to catalyze the asymmetric hydrogenation reaction of 1-acetophenone to prepare the R-1- (naphthalene-1-yl) ethanol product with higher chiral purity and can ensure higher conversion rate, and possible reasons are as follows: the electron-donating property of the naphthalene ring is combined with the special chiral center structure of the catalyst, so that the hydrogenation reaction is facilitated, and the selectivity of the chiral center is improved in the hydrogenation reaction process. Meanwhile, the preparation method can carry out reaction under the condition of lower pressure, has low requirement on equipment and is convenient for large-scale production and application.

In addition, after the asymmetric hydrogenation reaction is finished, the catalyst can be separated and removed from a reaction product through simple filtration, the risk of metal residue is well solved, the recovery rate is high, the catalyst can be recycled, and the synthesis cost of a final product medicament (such as cinacalcet) is reduced.

Detailed Description

The process for producing R-1- (naphthalen-1-yl) ethanol according to the present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The term "alkyl" as used herein refers to a saturated hydrocarbon containing a primary (normal) carbon atom, or a secondary carbon atom, or a tertiary carbon atom, or a quaternary carbon atom, or a combination thereof. Phrases containing such terms, such as "C1-C12 alkyl" refer to alkyl groups containing 1 to 12 carbon atoms, which may be, independently at each occurrence, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl, C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl. Suitable examples include, but are not limited to: methyl, ethyl, 1-propyl, 2-propyl (i-Pr, i-propyl, -CH (CH)₃)₂) 1-butyl (n-Bu, n-butyl, -CH)₂CH₂CH₂CH₃) 2-methyl-1-propyl (i-Bu, i-butyl, -CH)₂CH(CH₃)₂) 2-butyl (s-Bu, s-butyl, -CH (CH)₃)CH₂CH₃) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)₃)₃) 1-pentyl (n-pentyl, -CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-methyl-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) 1-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃And octyl (- (CH)₂)₇CH₃) N-nonyl.

The embodiment of the invention provides a preparation method of R-1- (naphthalene-1-yl) ethanol (compound 1), which has the following reaction formula:

carrying out asymmetric hydrogenation reaction on the 1-acetophenone under the catalysis of a catalyst;

the catalyst has the structural characteristics shown as the following formula (I):

wherein the content of the first and second substances,represents a bisphosphine ligand;

x is selected from-Cl, -Br, -I or-H; y is selected from-Cl, -Br or-I;

r is selected from-H or C1-C12 alkyl.

According to the preparation method, the appropriate catalyst is adopted to catalyze the asymmetric hydrogenation reaction of the 1-acetonaphthone to prepare the R-1- (naphthalene-1-yl) ethanol, the chiral purity of the prepared R-1- (naphthalene-1-yl) ethanol product is higher, and the higher conversion rate can be ensured, and the possible reasons are that: the electron-donating property of the naphthalene ring is combined with the special chiral center structure of the catalyst, so that the hydrogenation reaction is facilitated, and the selectivity of the chiral center is improved in the hydrogenation reaction process. Meanwhile, the preparation method can carry out reaction under the condition of lower pressure, has low requirement on equipment and is convenient for large-scale production and application.

In addition, the preparation method has the advantages of easily obtained raw materials, easy product separation, simple, convenient and safe reaction operation, less three wastes, simple and easy treatment and environment-friendly green synthesis process. Finally, a large number of experiments prove that the process has high and stable yield and low production cost, and is suitable for industrial production.

The R-1- (naphthalene-1-yl) ethanol can be subjected to sulfonylation and aminolysis to prepare an important intermediate R-1- (naphthalene-1-yl) ethylamine of cinacalcet.

In one specific embodiment, in the formula (I), the polymerization degree of PEG (polyethylene glycol) is 400-2000. Preferably, in the formula (I), the polymerization degree of PEG (polyethylene glycol) is 800-1200. By adopting PEG (polyethylene glycol) with proper polymerization degree as the solid-phase carrier of the catalyst, the influence of the introduction of the solid-phase carrier on the conversion rate of asymmetric catalytic reaction can be reduced, and the recovery rate of the catalyst is higher. Specifically, in formula (I), the degree of polymerization of PEG (polyethylene glycol) includes, but is not limited to, the following: 800. 850, 900, 950, 1000, 1100, 1200.

In one specific embodiment, the asymmetric hydrogenation reaction comprises the steps of:

dissolving the 1-acetonaphthone by a solvent, adding alkali and the catalyst, and introducing hydrogen for reaction.

Preferably, the hydrogen is introduced to carry out the reaction under the condition that the pressure is 0-7 atm. Under the pressure range, the asymmetric hydrogenation reaction can be effectively promoted, the higher reaction conversion rate is ensured, the condition is mild, and the preparation method is applied to large-scale industrial application. More preferably, in one embodiment, the hydrogen is introduced to allow the reaction to be carried out under a pressure of 2 to 5 atm. Specifically, the pressures include, but are not limited to, the following: 0atm, 1atm, 2atm, 2.5atm, 3atm, 3.5atm, 4atm, 5atm, 6atm, 7atm, 8 atm. It is understood that when the pressure is 0, it means that hydrogen just fills the reactor, but does not cause additional pressure to the reactants.

In one specific embodiment, before introducing the hydrogen, the reaction system is deaerated and degassed by inert gas, and then the inert gas is replaced by introducing the hydrogen to form a hydrogen atmosphere.

Preferably, the temperature of the reaction is 35-45 ℃. Under the temperature range, the method can not only ensure higher asymmetric selectivity, but also effectively promote the asymmetric hydrogenation reaction and improve the reaction conversion rate.

In one specific embodiment, the base is selected from at least one of potassium tert-butoxide, potassium ethoxide, and sodium ethoxide. Preferably, the base is potassium ethoxide.

In one specific embodiment, the solvent is selected from at least one of ethanol, methanol, isopropanol, toluene, and dichloromethane. Preferably, the solvent is toluene.

In one particular embodiment, the bisphosphine ligand is triphenylphosphine, BINAP, Diop, a bisphosphine analog with a dinaphthyl or substituted dinaphthyl, a bisphosphine analog with ferrocene or substituted ferrocene. Preferably, the bisphosphine ligand is a Diop.

As the catalyst, it is a P-BIAMH catalyst system. In one specific embodiment, R is methyl, ethyl, n-butyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl, 3, 5-dimethylbenzyl, or 1-naphthyl. Preferably, R is selected from C1-C3 hydrocarbyl groups. More preferably, R is methyl.

In one particular embodiment, X is selected from-Cl or-Br, preferably-Cl.

In one particular embodiment, Y is selected from-Cl or-Br, preferably-Cl.

In one particular embodiment, the catalyst structure is as follows:

the embodiment of the invention also provides a synthetic method of R-1- (naphthalene-1-yl) ethylamine, which comprises the following steps:

r-1- (naphthalen-1-yl) ethanol was synthesized according to the synthetic method described above;

and (3) sulfonylating and aminolysis are carried out on the R-1- (naphthalene-1-yl) ethanol.

R-1- (naphthalen-1-yl) ethylamine is an important intermediate of the chiral drug cinacalcet. Specifically, the reaction process of the synthesis method of the R-1- (naphthalene-1-yl) ethylamine is as follows:

the invention also provides a synthetic method of cinacalcet, which comprises the following steps: r-1- (naphthalen-1-yl) ethylamine was synthesized using the synthetic method described above.

Cinacalcet, the first drug in a new class of compounds called calcimimetics (calcimetics), activates the calcium receptor in the parathyroid gland, thereby reducing parathyroid hormone (PTH) secretion, thereby effectively delaying the progression of cardiovascular calcification, reducing the incidence of cardiovascular events, and improving all-cause mortality. Meanwhile, cinacalcet can also effectively reduce the product of PTH, calcium, phosphorus, calcium and phosphorus of SHPT dialysis patients, reduce the bone formation rate and improve bone diseases. The method for synthesizing the important intermediate of cinacalcet can effectively improve the chiral purity of cinacalcet, has important significance for improving the drug effect and reducing side effects undoubtedly, has high conversion rate of raw materials, is convenient for mild reaction conditions of industrial application, and is beneficial to cost reduction and large-scale popularization.

The following specific examples are provided, and the raw materials used in the examples are all commercially available unless otherwise specified.

The catalysts used in the following examples are all RuCl₂[(R,R)-diop][(R)-Me-P-BIMAH]The structure is as follows: