CN110551069B - Synthesis method of 5-phenylpentanol compound and intermediate thereof - Google Patents
Synthesis method of 5-phenylpentanol compound and intermediate thereof Download PDFInfo
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Abstract
The invention discloses a method for synthesizing a 5-phenylpentanol compound and an intermediate thereof. The synthesis method comprises the following steps: in a solvent under the action of an organic base and in Cu (CH) 3 CN) 4 PF 6 And (S) -DTBM-SEGPHOS, the compound 1 and the compound 2 are reacted as shown below to obtain a compound 3. The positive progress effects of the invention are as follows: obtaining a chiral intermediate through asymmetric catalytic prochiral substrate reaction, and obtaining a 5-phenylpentanol compound 6 through simple conversion; 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; successfully realizes high reactivity, high regioselectivity, high diastereoselectivity and high enantioselectivity, has simple post-treatment and is suitable for industrial production.
Description
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 neurogenic inflammation, pain transmission, and regulation of immune response in vivo (Harrison, T.; williams, B.J.; swain, C.J.; ball, R.G. Bioorg.Med.Chem.Lett.1994,4, 2545-2550), and antagonists of the corresponding substance P have potential clinical effects on migraine, rheumatoid arthritis, inflammatory bowel disease, and the like (Desai, M.C.; lefkowitz, S.L. Thadeio, P.F.; longo, K.P.; snider, R.M.J. Med.Chem.1992,35, 4911-4913). (+) -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, 3307-3310), in which (+) -CP-99,994 has an in vitro affinity to the NK-1 receptor of human IM-9 cells of 0.17 + -0.04 nM (Desai, M.C.; lefkowitz, S.L.; thadei, P.F.; longo, K.P.; snider, R.M.J.Med.Chem.1992.35, 4911-4913). (+) -CP-99,994 and (+) -L-733,060 have attracted the interest of 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.; udahyay, P.K.; kumar, P.tetrahedron Lett.2004,45,987-988 and Liu, Y. -W.; mao, Z. -Y.; ma R. -J.; yan J. -H.; si, C. -M.; wei, B. -G.tetrahedron 2017,73,2100-2108) is synthesized, and the structure of the 5-phenylpentanol compound 6 is as follows:
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-inserted Mannich type 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 synthesis method of a compound 3, which comprises the following steps: in a solvent under the action of an organic base and in Cu (CH) 3 CN) 4 PF 6 And (S) -DTBM-SEGPHOS, carrying out the following reaction on the compound 1 and the compound 2 to obtain a 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, 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 molar ratio thereof to the compound 1 is preferably 15 to 25L/mol, for example: 19.5L/mol.
In the synthesis of compound 3, the organic base may be a conventional solvent in the art for carrying out such reactions, preferably TEA, cy 2 One or more of NMe, DIPEA, TMG and Barton's base, more preferably TEA. The organic base may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, it is used in a molar ratio of 0.02 to 0.1 to the compound 1,for example, 0.05.
In the synthesis of compound 3, the Cu (CH) 3 CN) 4 PF 6 The amount of (b) may be an amount conventionally used in the art for carrying out such a reaction, and is preferably in a molar ratio of 0.02 to 0.1, for example, 0.05, to the compound 1.
In the method for synthesizing the compound 3, the (S) -DTBM-SEGPHOS can be used in an amount conventionally used in the art for carrying out such a reaction, and preferably, the molar ratio thereof to the compound 1 is 0.02 to 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 temperature of the reaction 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 compound 3, a preferred synthetic method of compound 3 comprises the steps of: mixing Cu (CH) 3 CN) 4 PF 6 And (S) -DTBM-SEGPHOS is mixed with a solvent, then mixed with a compound 1 and a compound 2, and then mixed with the organic base to carry out the reaction to prepare a compound 3. Preferably, cu (CH) is added under anhydrous conditions 3 CN) 4 PF 6 And (S) -DTBM-SEGPHOS is mixed with a solvent, the compound 1 and the compound 2 are added, and the organic base is added for reaction. The addition temperature of the organic base is preferably 0 ℃ to-60 ℃, for example, -40 ℃.
In the synthesis of compound 3, the progress of the reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and generally the end point of the reaction is the disappearance of 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 molar ratio thereof to the compound 3 is preferably 8.0 to 20L/mol, for example: 11.49L/mol.
In the synthesis of compound 4, the silver salt may be a conventional silver salt used in the art for such reactions, preferably AgTFA, agOTf, agBF 4 Or AgSCF 3 One or more of (a); the silver salt may be used in an amount conventional in the art for carrying out such reactions, preferably in a molar ratio to compound 3 of from 1.0 to 2.0, e.g., 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 method for synthesizing 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 the disappearance of the compound 3, and the reaction time is preferably 6 to 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 to 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 molar ratio thereof to the compound 4 is preferably 12 to 20L/mol, for example: 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 may be used in an amount conventionally used in the art for carrying out such a reaction, and preferably in a molar ratio to the compound 4 of 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 of compound 5, the progress of the reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and generally the end point of the reaction is the disappearance of compound 4, and the reaction time is preferably 1 to 5 hours, e.g., 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 the 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 molar ratio of the compound to the compound 5 is preferably 10.5 to 26.3L/mol, for example: 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 thereof to the compound 5 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: 2mol/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 synthesis of compound a, the progress of the hydrolysis reaction can be detected by a monitoring method (e.g., TLC, HPLC, or NMR) which is conventional in the art, and generally the end point of the reaction is determined when compound 5 disappears, 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: in a solvent, compound A prepared as described above was mixed with (Boc) 2 O is reacted as shown below to obtain 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 may be used in an amount conventional in the art for carrying out such reactions, preferably in a volume molar ratio to compound a of from 15 to 25L/mol, for example: 21.05L/mol.
In the synthesis of 5-phenylpentanol compound 6, the said (Boc) 2 The amount of O may be that conventionally used in the art for carrying out such reactions, and is preferably in a molar ratio to compound A of from 1.0 to 2.0, e.g., 1.2. Said (Boc) 2 The temperature at which O is added dropwise may be a temperature conventional in the art for carrying out such a reaction, and is preferably from-5 ℃ to 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 monitoring method (such as TLC, HPLC or NMR) which is conventional in the art, and generally the time when the compound A disappears is taken as a reaction end point, and the reaction time is preferably 10 to 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 bromocrotonic acid is used as a substrate and directly reacts with aldimine to generate vinylon Mannich type reaction, 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. Experimental procedures without specifying specific conditions in the following examples were selected in accordance with conventional procedures and conditions, or in accordance with 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.
Example 1
Compound 1: adding a compound (E) -1- (3,5-diphenylyl-1H-pyrazol-1-yl) but-2-en-1-one (Sibi, M.P.; itoh, K.J.Am.Chem.Soc.2007,129, 8064-8065.) (30mmol, 8.65g) into a dry 250mL eggplant-shaped bottle, adding 100mL of carbon tetrachloride to dissolve, then adding NBS (36mmol, 6.41g) and AIBN (0.9mmol, 148mg) in sequence, freezing the solution for three times to remove oxygen, recovering the room temperature, heating to 90 ℃ under nitrogen protection, refluxing for 12H, naturally cooling to room temperature, filtering, washing filter residues with a small amount of carbon tetrachloride, concentrating the filtrate, and performing column chromatography (PE: EA =80 1) to obtain a product 1 (white solid, 6.7g, 61%).
1 H NMR(400MHz,CDCl 3 )δ7.95-7.85(m,2H),7.67(d,J=15.3Hz,1H),7.53-7.34(m,8H),7.23-7.15(dd,J=7.6Hz,15.3Hz,1H),4.13(d,J=7.5Hz,2H)ppm. 13 C NMR(100MHz,CDCl 3 )δ163.33,153.76,147.71,143.75,131.53,130.94,129.37,128.97,128.91,128.86,127.96,126.33,124.22,110.39,29.47ppm.MS(ESI,M+H + ):367.05.HRMS(ESI,M+H + ):m/z calcd.367.0441,found367.0439.
Compound 3: cu (CH) was weighed into an oven-dried 100mL Schlenk flask in a glove box 3 CN) 4 PF 6 (55.9mg, 0.15mmol) and (S) -DTBM-SEGPHOS (177mg, 0.15mmol), bi Yichu were weighed as glove boxes, THF (58.5 mL) was added, stirring was carried out at room temperature for 15min, 1 (1.10g, 3.0mmol) and aldimine 2 (1.23g, 6.0mmol) were added, and the mixture was cooled in a cold bath at-40 ℃. Finally TEA solution (0.1m in thf,1.5 ml) was added, reacted at 40 ℃ for 48 hours and directly separated by column chromatography (PE: EA =10: 1) to give product 3 (white solid, 1.53g,89%,11/1dr,>99%ee)。 1 H NMR(400MHz,CDCl 3 )δ7.94-7.89(m,2H),7.67(d,J=15.3Hz,1H),7.49-7.40(m,8H),7.36-7.27(m,5H),7.27-7.21(m,1H),6.76(s,1H),5.37(d,J=8.53Hz,1H),5.18-4.99(m,2H),1.42(s,9H)ppm. 13 C NMR(100MHz,CDCl 3 )δ163.16,154.95,153.77,147.72,145.01,131.52,130.93,129.38,129.01,128.92,128.84,128.65,128.16,127.94,127.56,126.74,126.37,123.60,110.43,80.48,57.63,56.48,28.31ppm.MS(ESI,M+Na + ):594.05.HRMS(ESI,M+H + ):m/zcalcd.572.1543,found 572.1533.
compound 4: to the dried 100mL vial seals in a glovebox are weighed AgTFA (289mg, 1.3mmol) and compound 3 (500mg, 0.87mmol), bi Yichu, and added CH 3 CN (10 mL), placing the sealed tube in an oil bath at 50 ℃, heating for 8 hours for reaction, naturally cooling, filtering the reaction solution by using kieselguhr, concentrating the filtrate, performing flash column chromatography (PE/EA = 2/1) to obtain a compound 4 (white solid, 349mg,92 percent,>20/1dr)。 1 H NMR(400MHz,CDCl 3 )δ7.94-7.87(m,2H),7.72-7.63(dd,J=15.6Hz,1H),7.51-7.15(m,13H),6.72(s,1H),6.55-6.46(dd,J=15.6Hz,1H),6.14-6.07(b,1H),5.61-5.55(ddd,1H),5.14-5.08(dd,J=8.6Hz,1H)ppm. 13 CNMR(100MHz,CDCl 3 )δ162.71,158.83,153.71,147.55,141.86,135.56,131.37,130.85,129.39,129.18,129.13,128.85,127.89,126.80,126.35,123.47,110.40,79.36,59.74ppm.MS(ESI,M+Na + ):458.10.HRMS(ESI,M+Na + ):m/z calcd.458.1475,found 458.1483.
compound 5: compound 4 (218mg, 0.50mmol) was added to a 25mL eggplant-shaped bottle, and THF/H was added thereto 2 O (6.4 mL/1.6 mL), naBH was added slowly at 0 deg.C 4 (151mg, 4.0mmol), naturally returning the reaction system to room temperature, continuously reacting at room temperature for 3 hours, adding hydrochloric acid (1M, 20mL) to quench, extracting with DCM for three times, combining organic phases, drying with anhydrous sodium sulfate, concentrating, and performing flash column chromatography (PE/EA = 1:1-1:2) to obtain a compound 5 (white solid, 91.5mg,83%,>20/1dr)。 1 H NMR(400MHz,CDCl 3 )δ7.46-7.16(m,5H),5.40(s,1H),4.96-4.83(m,2H),3.62-3.44(m,2H),1.75-1.46(m,2H),1.34-1.17(m,2H)ppm. 13 C NMR(100MHz,CDCl 3 )δ159.11,136.59,128.88,127.06,80.95,61.97,59.67,28.92,27.65ppm.MS(ESI,M+Na + ):244.00.HRMS(ESI,M+H + ):m/z calcd.222.1125,found 222.1126.
compound 6: compound 5 (85mg, 0.38mmol) was added to a 25mL eggplant-shaped bottle, and CH was added thereto 3 OH (8 mL), KOH solution (2.4mL, 2M) was added thereto, the reaction mixture was subjected to an oil bath at 80 ℃ for 16 hours, then cooled to room temperature, DCM (20 mL) was added to the reaction mixture to dilute the reaction mixture, anhydrous magnesium sulfate was added thereto, drying and suction filtration were carried out, the filtrate was concentrated and CHCl was added thereto 3 Dissolving, and adding dropwise (Boc) at 0 deg.C 2 O (100mg, 0.46mmol), naturally returning to room temperature, continuing the reaction for 12 hours,the reaction solution is quenched by adding water, extracted three times by DCM, and the organic phases are respectively saturated NaHCO 3 The solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated and subjected to flash column chromatography (PE/EA = 1/1) to obtain compound 6 (white solid, 82mg,73%,>20/1dr)。 1 H NMR(400MHz,CDCl 3 )δ7.38-7.30(m,5H),5.66-5.51(b,1H),4.72-4.58(b,1H),3.97-3.82(b,1H),3.69-3.48(m,2H),3.24-2.60(b,2H),1.76-1.53(m,4H),1.43(s,9H)ppm. 13 C NMR(100MHz,CDCl 3 )δ155.73,138.48,128.40,127.79,127.55,79.75,74.05,62.51,59.26,30.90,29.22,28.36ppm.MS(ESI,M+Na + ):318.10.HRMS(ESI,M+H + ):m/z calcd.296.1856,found 296.1857。
Claims (19)
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 TEA and Cy 2 One or more of 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, said Cu (CH) 3 CN) 4 PF 6 The mol ratio of the compound 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 0-60 ℃.
3. The method of synthesis according to claim 2,
the solvent is tetrahydrofuran;
and/or the organic base is TEA;
and/or, the synthesis method of the compound 3 comprises the following steps: mixing Cu (CH) 3 CN) 4 PF 6 And (S) -DTBM-SEGPHOS is mixed with a solvent, then mixed with a compound 1 and a compound 2, and then mixed with the organic base to carry out the reaction to prepare a compound 3.
4. The method of synthesis according to claim 3,
the synthesis method of the compound 3 comprises the following steps: adding Cu (CH) under anhydrous condition 3 CN) 4 PF 6 Mixing (S) -DTBM-SEGPHOS with a solvent, adding a compound 1 and a compound 2, and then adding the organic base to carry out the reaction to obtain a compound 3; the adding temperature of the organic alkali is 0-60 ℃.
6. the method of synthesis according to claim 5,
the solvent is a nitrile solvent;
and/or the volume mol ratio of the solvent to the compound 3 is 8.0-20L/mol;
and/or the silver salt is AgTFA, agOTf or AgBF 4 Or AgSCF 3 One or more of;
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: the reaction is carried out by adding a solvent to the mixture of compound 3 and the silver salt to produce compound 4.
7. The method of synthesis according to claim 6,
the solvent is acetonitrile;
and/or, the synthesis method of the compound 4 comprises the following steps: under anhydrous condition, compound 3 and silver salt are mixed, solvent is added, and the reaction is carried out to obtain compound 4.
8. 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 any one of claims 5 to 7;
9. the method of synthesis according to claim 8,
the solvent is a mixed solvent of an organic solvent and water;
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;
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.
10. The method of synthesis according to claim 9,
the organic solvent is an alcohol solvent and/or an ether solvent;
the volume ratio of the organic solvent to the water in the mixed solvent is 2:1 to 6:1;
and/or the reducing agent is sodium borohydride.
11. The method of synthesis according to claim 10,
when the organic solvent is an alcohol solvent, the alcohol solvent is one or more of methanol, ethanol and isopropanol;
when the organic solvent is an ether solvent, the ether solvent is tetrahydrofuran.
12. 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 any one of claims 8 to 11;
13. the method of synthesis according to claim 12,
the solvent is an alcohol solvent and/or an ether solvent;
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;
and/or the inorganic base participates in the reaction in the form of aqueous solution of the inorganic base;
and/or the temperature of the hydrolysis reaction is 60-100 ℃.
14. The method of synthesis according to claim 13,
when the solvent is an alcohol solvent, the alcohol solvent is one or more of methanol, ethanol and isopropanol; when the solvent is an ether solvent, the ether solvent is tetrahydrofuran;
and/or, the inorganic alkali is sodium hydroxide and/or potassium hydroxide;
and/or the molar concentration of the aqueous solution of the inorganic base is 1 mol/L-10 mol/L.
15. The method of synthesis according to claim 14,
the molar concentration of the aqueous solution of the inorganic base is 1-5 mol/L.
16. A method for synthesizing a 5-phenylpentanol compound 6 is characterized by comprising the following steps: in a solvent, compound A is reacted with (Boc) 2 O is reacted as shown below to obtain 5-phenylpentanol compound 6; the synthesis method of the compound A is as described in any one of claims 12 to 15;
17. the method of synthesis according to claim 16,
the solvent is halogenated hydrocarbon solvent and/or ether solvent;
and/or the volume mol ratio of the organic solvent to the compound A is 15-25L/mol;
and/or, said (Boc) 2 The molar ratio of O to the compound A is 1.0-2.0;
and/or, said (Boc) 2 The dripping temperature of O is-5 ℃ to 5 ℃;
and/or the temperature of the reaction is room temperature.
18. The method of synthesis according to claim 17,
when the solvent is halogenated hydrocarbon solvent, the halogenated hydrocarbon solvent is chloroform; when the solvent is an ether solvent, the ether solvent is tetrahydrofuran.
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