阅读说明：本技术 一种5-苯基戊醇类化合物及其中间体的合成方法 (synthesis method of 5-phenylpentanol compound and intermediate thereof ) 是由 殷亮 钟锋 于 2018-05-31 设计创作，主要内容包括：本发明公开了一种5-苯基戊醇类化合物及其中间体的合成方法。本发明的合成方法包括下述步骤：在溶剂中,在有机碱的作用下,在Cu(CH<Sub>3</Sub>CN)<Sub>4</Sub>PF<Sub>6</Sub>和(S)-DTBM-SEGPHOS的作用下,将化合物1和化合物2进行如下所示的反应得到化合物3即可。本发明的积极进步效果在于：通过不对称催化前手性底物反应得到手性中间体,经过简单转化后得到5-苯基戊醇类化合物6；关键反应所用催化剂廉价易得,用量低,反应条件温和,所涉及路线简单,产物产率和纯度高；成功实现了高反应性、高区域选择性、高非对映选择性、高对映选择性,后处理简单,适于工业化生产。<Image he="240" wi="700" file="DDA0001680398450000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a synthesis method of a 5-phenylpentanol compound and an intermediate thereof, which comprises the following steps of carrying out the following reaction on a compound 1 and a compound 2 in a solvent under the action of organic base and Cu (CH 3 CN) 4 PF 6 and (S) -DTBM-SEGPHOS to obtain a compound 3)

1. A method for synthesizing a compound 3 is characterized by comprising the steps of reacting a compound 1 with a compound 2 in a solvent under the action of an organic base and under the action of Cu (CH ₃ CN) ₄ PF ₆ and (S) -DTBM-SEGPHOS to obtain the compound 3;

2. The method of synthesis according to claim 1,

the solvent is an ether solvent;

and/or the volume mol ratio of the solvent to the compound 1 is 15-25L/mol;

And/or the organic base is one or more of TEA, Cy ₂ NMe, DIPEA, TMG and Barton's base;

And/or the molar ratio of the organic base to the compound 1 is 0.02-0.1;

And/or the molar ratio of the Cu (CH ₃ CN) ₄ PF ₆ to the compound 1 is 0.02-0.1;

And/or the molar ratio of the (S) -DTBM-SEGPHOS to the compound 1 is 0.02-0.1;

And/or the molar ratio of the compound 2 to the compound 1 is 1.0-3.0;

And/or, the reaction is carried out under anhydrous conditions;

And/or the temperature of the reaction is 0 ℃ to-60 ℃.

3. The method of synthesis according to claim 2,

The solvent is tetrahydrofuran;

and/or the organic base is TEA;

and/or, the synthetic method of the compound 3 comprises the following steps of mixing Cu (CH ₃ CN) ₄ PF ₆ and (S) -DTBM-SEGPHOS with a solvent, then mixing with the compound 1 and the compound 2, and then mixing with the organic base to carry out the reaction to obtain the compound 3, preferably mixing Cu (CH ₃ CN) ₄ PF ₆ and (S) -DTBM-SEGPHOS with the solvent under the anhydrous condition, adding the compound 1 and the compound 2, and then adding the organic base to carry out the reaction, wherein the adding temperature of the organic base is preferably 0-60 ℃.

4. a method for synthesizing a compound 4, which is characterized by comprising the following steps: in a solvent, the compound 3 and a silver salt react as shown below to obtain a compound 4; the synthesis method of the compound 3 is as described in any one of claims 1 to 3;

5. The method of synthesis according to claim 4,

The solvent is a nitrile solvent, preferably acetonitrile;

And/or the volume mol ratio of the solvent to the compound 3 is 8.0-20L/mol;

and/or the silver salt is one or more of AgTFA, AgOTf, AgBF ₄ or AgSCF ₃;

And/or the molar ratio of the silver salt to the compound 3 is 1.0-2.0;

And/or, the reaction is carried out under anhydrous conditions;

And/or the reaction temperature is 40-60 ℃;

And/or, the synthesis method of the compound 4 comprises the following steps: adding a solvent into the mixture of the compound 3 and the silver salt, and carrying out the reaction to obtain a compound 4; preferably, the reaction is carried out by mixing compound 3 and a silver salt under anhydrous conditions and adding a solvent.

6. A method for synthesizing a compound 5, which is characterized by comprising the following steps: in a solvent, carrying out the reaction shown as the following on the compound 4 under the action of a reducing agent to obtain a compound 5; the synthesis method of the compound 4 is as described in claim 4 or 5;

7. the method of synthesis according to claim 6,

the solvent is a mixed solvent of an organic solvent and water; the organic solvent is preferably an alcohol solvent and/or an ether solvent; the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol; the ether solvent is preferably tetrahydrofuran; the volume ratio of the organic solvent to the water in the mixed solvent is preferably 2: 1-6: 1;

and/or the volume mol ratio of the solvent to the compound 4 is 12-20L/mol;

and/or the reducing agent is borohydride of alkali metal, preferably sodium borohydride;

And/or the molar ratio of the reducing agent to the compound 4 is 6.0-10.0;

and/or the temperature of the reaction is room temperature.

8. A method for synthesizing a compound A, which is characterized by comprising the following steps: under the action of inorganic base, carrying out hydrolysis reaction on the compound 5 as shown in the specification to obtain a compound A; the synthesis method of the compound 5 is as described in claim 6 or 7;

9. The method of synthesis according to claim 8,

The solvent is an alcohol solvent and/or an ether solvent; the alcohol solvent is preferably one or more of methanol, ethanol and isopropanol; the ether solvent is preferably tetrahydrofuran;

And/or the volume mol ratio of the solvent to the compound 5 is 10.5-26.3L/mol;

and/or, the inorganic base is hydroxide of alkali metal, preferably sodium hydroxide and/or potassium hydroxide;

And/or the inorganic base participates in the reaction in the form of aqueous solution of the inorganic base; the molar concentration of the aqueous solution of the inorganic base is preferably 1 to 10mol/L, more preferably 1 to 5 mol/L;

and/or the temperature of the hydrolysis reaction is 60-100 ℃.

10. A method for synthesizing 5-phenylpentanol compound 6, which comprises the steps of reacting compound A with (Boc) ₂ O in a solvent to obtain 5-phenylpentanol compound 6, wherein the method for synthesizing compound A is as defined in claim 8 or 9;

11. The method of synthesis according to claim 10,

the solvent is halogenated hydrocarbon solvent and/or ether solvent; the halogenated hydrocarbon solvent is preferably chloroform; the ether solvent is preferably tetrahydrofuran;

and/or the volume mol ratio of the organic solvent to the compound A is 15-25L/mol;

and/or the molar ratio of the (Boc) ₂ O to the compound A is 1.0-2.0;

And/or the dropping temperature of the (Boc) ₂ O is-5 ℃;

and/or the temperature of the reaction is room temperature.

12. A compound 3, 4 or 5 having the structure:

Technical Field

the invention relates to a method for synthesizing a 5-phenylpentanol compound and an intermediate thereof.

Background

Neurokinin substance P is involved in biological responses such as neuroinflammation, pain transmission, and regulation of immune responses in vivo (Harrison, T.; Williams, B.J.; Swain, C.J.; Ball, R.G. Bioorg.Med.Chem.Lett.1994,4, 2545-. (+) -CP-99,994 and (+) -L-733,060 are potent and selective neurokinin substance P receptor antagonists (Liu, R. -H.; Fang, K.; Wang, B.; Xu, M. -H.; Lin, G. -Q.J.Org.Chem.2008,73, 3307-. (+) -CP-99,994 and (+) -L-733,060 have attracted interest to organic synthesizers. In the synthesis work, a chiral substrate is mainly used, the chirality of the product is controlled through the substrate, the obtained chiral substrate is generally obtained through chiral resolution, the process is complicated, and the 5-phenylpentanol compound 6 of (+) -CP-99,994 and (+) -L-733,060 (Mandar, S.B.; Upadhyy, P.K.; Kumar, P.tetrahedron Lett.2004,45, 987-:

In organic synthesis, vinylogous Mannich type reactions can be induced by chirality to generate stereoselective products. The traditional vinylogous reaction needs to prepare a substrate into dienol silyl ether in advance, equivalent silicon waste is generated after the reaction, and the atom economy is poor.

Therefore, the development of asymmetric direct vinylogous Mannich type reaction, and the realization of high reactivity, high regioselectivity, high diastereoselectivity and high enantioselectivity are the problems to be solved in the field.

disclosure of Invention

The invention provides a synthetic method of a 5-phenylpentanol compound and an intermediate thereof, aiming at overcoming the defects of more waste materials, poor atom economy and the like in a vinylon Mannich reaction in the prior art. The method has the following advantages: obtaining a chiral intermediate through asymmetric catalytic prochiral substrate reaction, and obtaining a 5-phenylpentanol compound 6 through simple conversion; the used catalyst is cheap and easy to obtain, the catalyst dosage is low, the reaction condition is mild, the related route is simple, and the product yield and purity are high; pyrazole amide of bromocrotonic acid is used as a substrate, and directly reacts with aldimine to carry out vinylon Mannich type reaction, so that high reactivity, high regioselectivity, high diastereoselectivity and high enantioselectivity are realized, the post-treatment is simple, and the method is suitable for industrial production.

The invention provides a method for synthesizing a compound 3, which comprises the following steps of carrying out the following reaction on a compound 1 and a compound 2 in a solvent under the action of organic base and Cu (CH ₃ CN) ₄ PF ₆ and (S) -DTBM-SEGPHOS to obtain the compound 3;

In the synthesis method of compound 3, the solvent may be a conventional solvent in the art for performing such a reaction, preferably an ether solvent, and more preferably tetrahydrofuran. The amount of the solvent can be the conventional amount for carrying out the reaction in the field as long as the reaction is not influenced; the volume mol ratio of the compound to the compound 1 is preferably 15-25L/mol, such as: 19.5L/mol.

in the synthesis method of the compound 3, the organic base can be a conventional solvent for performing such reactions in the field, preferably one or more of TEA, Cy ₂ NMe, DIPEA, TMG and Barton's base, more preferably TEA, and the organic base can be used in an amount conventional for performing such reactions in the field, preferably, the molar ratio of the organic base to the compound 1 is 0.02-0.1, for example, 0.05.

in the synthesis method of the compound 3, the amount of the Cu (CH ₃ CN) ₄ PF ₆ can be the amount conventionally used in the art for carrying out such reactions, and is preferably 0.02 to 0.1, for example, 0.05 in terms of molar ratio to the compound 1.

In the synthesis method of the compound 3, the (S) -DTBM-SEGPHOS can be used in the conventional amount for carrying out the reaction in the field, and the molar ratio of the (S) -DTBM-SEGPHOS to the compound 1 is preferably 0.02-0.1, for example, 0.05.

in the synthesis method of the compound 3, the compound 2 can be used in an amount which is conventional in the art for carrying out such reactions, and preferably the molar ratio of the compound 2 to the compound 1 is 1.0-3.0, for example, 2.0.

in the synthesis method of the compound 3, the reaction is preferably carried out under anhydrous conditions.

in the method for synthesizing compound 3, the reaction temperature may be a temperature conventionally used in the art for carrying out such a reaction, and is preferably 0 ℃ to-60 ℃, for example, -40 ℃.

Among the synthetic methods of the compound 3, the preferred synthetic method of the compound 3 includes the steps of mixing Cu (CH ₃ CN) ₄ PF ₆, (S) -DTBM-SEGPHOS with a solvent, then mixing with the compound 1 and the compound 2, and then mixing with the organic base to perform the reaction to obtain the compound 3, the preferred method is to mix Cu (CH ₃ CN) ₄ PF ₆, (S) -DTBM-SEGPHOS with a solvent, add the compound 1 and the compound 2, and then add the organic base to perform the reaction under anhydrous conditions, and the addition temperature of the organic base is preferably 0 ℃ to-60 ℃, for example, -40 ℃.

In the synthesis method of the compound 3, the progress of the reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the end point of the reaction is the disappearance of the compound 1, and the reaction time is preferably 24 to 60 hours, for example, 48 hours.

In the synthesis method of the compound 3, the reaction can further comprise post-treatment after the reaction is finished; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, concentrating and carrying out column chromatography to obtain a compound 3. The method and conditions for column chromatography may be those conventional in the art for such procedures.

the invention also provides a synthesis method of the compound 4, which comprises the following steps: in a solvent, the compound 3 prepared by the method and silver salt react to obtain a compound 4 as shown in the specification;

in the synthesis method of compound 4, the solvent may be a conventional solvent in the art for performing such a reaction, preferably a nitrile solvent, more preferably acetonitrile. The amount of the solvent can be the conventional amount for carrying out the reaction in the field as long as the reaction is not influenced; the volume mol ratio of the compound to the compound 3 is preferably 8.0-20L/mol, such as: 11.49L/mol.

in the synthesis method of the compound 4, the silver salt can be a conventional silver salt for carrying out the reaction in the field, preferably one or more of AgTFA, AgOTf, AgBF ₄ or AgSCF ₃, the dosage of the silver salt can be a conventional dosage for carrying out the reaction in the field, and the molar ratio of the silver salt to the compound 3 is preferably 1.0-2.0, for example, 1.49.

in the synthesis method of the compound 4, the reaction is preferably carried out under anhydrous conditions.

In the synthesis of compound 4, the reaction temperature may be a temperature conventional in the art for carrying out such a reaction, preferably 40 ℃ to 60 ℃, for example, 50 ℃.

Among the synthetic methods of compound 4, the preferred synthetic method of compound 4 comprises the following steps: the compound 3, silver salt and solvent are mixed and the reaction is carried out to obtain the compound 4. Preferably, the reaction is carried out by mixing compound 3 and a silver salt under anhydrous conditions and adding a solvent.

In the synthesis method of the compound 4, the progress of the reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the end point of the reaction is determined when the compound 3 disappears, and the reaction time is preferably 6-10 hours, for example, 8 hours.

In the synthesis method of the compound 4, the reaction can further comprise post-treatment after the reaction is finished; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, cooling, filtering, concentrating the filtrate, and carrying out column chromatography to obtain the compound 4. The method and conditions for column chromatography may be those conventional in the art for such procedures.

The invention also provides a synthesis method of the compound 5, which comprises the following steps: in a solvent, carrying out the reaction of the compound 4 prepared by the method under the action of a reducing agent to obtain a compound 5;

In the synthesis method of compound 5, the solvent may be a conventional solvent for performing such a reaction in the art, and preferably a mixed solvent of an organic solvent and water. The organic solvent is preferably an alcohol solvent and/or an ether solvent. The alcohol solvent is preferably one or more of methanol, ethanol and isopropanol. The ether solvent is preferably tetrahydrofuran. The volume ratio of the organic solvent to the water in the mixed solvent is preferably 2: 1-6: 1, e.g., 4: 1. the amount of the solvent can be the conventional amount for carrying out the reaction in the field as long as the reaction is not influenced; the volume mol ratio of the compound to the compound 4 is preferably 12-20L/mol, such as: 16.0L/mol.

in the synthesis of compound 5, the reducing agent may be a conventional reducing agent used in the art for performing such reactions, preferably a borohydride of an alkali metal, more preferably sodium borohydride. The reducing agent can be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, the molar ratio of the reducing agent to the compound 4 is 6.0 to 10.0, for example, 8.0.

In the synthesis method of compound 5, the reaction temperature may be a conventional temperature for performing such a reaction in the art, preferably room temperature.

the preferred synthesis method of compound 5 comprises the following steps: adding a reducing agent into a solution of the compound 4 and a solvent, and carrying out the reaction at the temperature to obtain a compound 5. The reducing agent may be added at a temperature conventional in the art for carrying out such reactions, preferably from-5 ℃ to 5 ℃, e.g., 0 ℃.

In the synthesis method of the compound 5, the progress of the reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the end point of the reaction is determined when the compound 4 disappears, and the reaction time is preferably 1 to 5 hours, for example, 3 hours.

in the synthesis method of the compound 5, the reaction can further comprise post-treatment after the reaction is finished; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, adding water to quench the reaction, extracting by using an organic solvent, drying, concentrating and carrying out column chromatography to obtain a compound 5. The method and conditions for column chromatography may be those conventional in the art for such procedures.

The invention also provides a synthesis method of the compound A, which comprises the following steps: under the action of inorganic base, compound 5 prepared by the method is subjected to hydrolysis reaction as shown in the specification to obtain compound A;

In the synthesis method of compound a, the solvent may be a conventional solvent for performing such a reaction in the art, and preferably an alcohol solvent and/or an ether solvent. The alcoholic solvent may be a conventional alcoholic solvent used in the art for such reactions, preferably one or more of methanol, ethanol and isopropanol. The ether solvent is preferably tetrahydrofuran. The amount of the solvent can be the conventional amount for carrying out the reaction in the field as long as the reaction is not influenced; the volume mol ratio of the compound to the compound 5 is preferably 10.5-26.3L/mol, such as: 21.05L/mol.

in the synthesis method of compound a, the inorganic base may be a conventional inorganic base used in the art for performing such a reaction, and is preferably an alkali metal hydroxide, more preferably sodium hydroxide and/or potassium hydroxide. The amount of the inorganic base can be the conventional amount for carrying out the reaction in the field as long as the reaction is not influenced; preferably, the molar ratio of the compound 5 to the compound is 8.0 to 15.0, for example, 12.6. The inorganic base is preferably present in the reaction in the form of an aqueous solution of the inorganic base. The aqueous solution of the inorganic base may have a molar concentration conventional in such reactions in the art, preferably from 1mol/L to 10mol/L, more preferably from 1mol/L to 5mol/L, for example: 2 mol/L.

in the synthesis of compound a, the temperature of the hydrolysis reaction may be a temperature conventional in the art for carrying out such a reaction, preferably 60 ℃ to 100 ℃, for example, 80 ℃.

in the method for synthesizing the compound a, the progress of the hydrolysis reaction can be detected by a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the time when the compound 5 disappears is used as a reaction end point, and the reaction time is preferably 12 to 20 hours.

In the synthesis method of the compound A, the hydrolysis reaction can further comprise post-treatment after the reaction is finished; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: and after the reaction is finished, cooling, adding an organic solvent for dilution, drying and concentrating to obtain the compound A.

the invention also provides a synthesis method of the 5-phenylpentanol compound 6, which comprises the following steps of carrying out the following reaction on the compound A prepared by the previous method and (Boc) ₂ O in a solvent to obtain the 5-phenylpentanol compound 6;

In the method for synthesizing the 5-phenylpentanol compound 6, the organic solvent can be a conventional organic solvent for carrying out such a reaction in the field, and is preferably a halogenated hydrocarbon solvent and/or an ether solvent. The halogenated hydrocarbon solvent is preferably chloroform. The ether solvent is preferably tetrahydrofuran. The organic solvent can be used in an amount which is conventional in the art for carrying out such a reaction, and preferably has a volume mol ratio of 15-25L/mol to the compound A, for example: 21.05L/mol.

In the synthesis method of the 5-phenylpentanol compound 6, the (Boc) ₂ O can be used in an amount which is conventional in the field for carrying out the reaction, preferably the molar ratio of the (Boc) ₂ O to the compound A is 1.0-2.0, for example, 1.2. the dropping temperature of the (Boc) ₂ O can be conventional in the field for carrying out the reaction, preferably-5 ℃, for example, 0 ℃.

In the method for synthesizing the 5-phenylpentanol compound 6, the reaction temperature can be a conventional temperature for performing such a reaction in the art, preferably room temperature.

In the method for synthesizing the 5-phenylpentanol compound 6, the progress of the reaction can be detected by a conventional monitoring method in the field (such as TLC, HPLC or NMR), the end point of the reaction is generally used when the compound A disappears, and the reaction time is preferably 10-20 hours.

In the synthesis method of the 5-phenylpentanol compound 6, the reaction can further comprise post-treatment after the reaction is finished; the work-up procedure is a conventional work-up procedure for such reactions, preferably comprising the following steps: after the reaction is finished, adding water to quench the reaction, extracting by an organic solvent, washing by water, drying, concentrating, and carrying out column chromatography to obtain the 5-phenylpentanol compound 6. The method and conditions for column chromatography may be those conventional in the art for such procedures.

The invention also provides an intermediate for synthesizing the 5-phenylpentanol compound 6, which has the following structure:

the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The preparation of the starting compound 2 used in the present invention is referred to in Kanazawa, a.m.; denis, j.; greene, A.E.J.org.chem.1984,59,1238-1240, other reagents and starting materials are commercially available.

in the present invention, the operation is carried out at room temperature unless otherwise specified. The room temperature is 0-35 ℃, preferably 20-30 ℃.

In the present invention, the Barton's Base is 2-tert-butyl-1, 1,3, 3-tetramethylguanidine (CAS: 29166-72-1); the TMG is tetramethylguanidine (CAS: 80-70-6).

the positive progress effects of the invention are as follows:

(1) Obtaining a chiral intermediate through asymmetric catalytic prochiral substrate reaction, and obtaining the 5-phenylpentanol compound 6 through simple conversion.

(2) the catalyst used in the key reaction is cheap and easy to obtain, the dosage is low, the reaction condition is mild, the related route is simple, and the yield and the purity of the product are high.

(3) Pyrazole amide of bromo-crotonic acid is used as a substrate to directly generate an vinylon-inserting Mannich type reaction with aldimine, so that high reactivity, high regioselectivity, high diastereoselectivity and high enantioselectivity are successfully realized, the post-treatment is simple, and the method is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the specific operation temperature is not limited, and it is meant to be carried out at room temperature (0 to 35 ℃ C.).

in the following examples calcd means the calculated value and found means the actual value.