CN112457204A - Preparation method of S-configuration phenethylamine hydrochloride compound - Google Patents
Preparation method of S-configuration phenethylamine hydrochloride compound Download PDFInfo
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Abstract
The invention relates to a preparation method of an S-configuration phenethylamine hydrochloride compound, which relates to the technical field of medicine synthesis and preparation and comprises the following steps: carrying out Friedel-crafts reaction on m-phenyl dimethyl ether and acetyl chloride under the condition of Lewis acid to generate an intermediate A; the intermediate A in the step (2) is not separated and then reacts with hydroxylamine hydrochloride to generate an intermediate B; reducing the intermediate B in the step (3) under the condition of a reducing agent to obtain a compound C; resolving the compound C in the step (4) with organic acid to obtain a compound D organic salt with an S configuration; and (5) dissociating the organic salt and then salifying to obtain a target product compound E. The preparation method has the characteristics of simple purification, low cost, high efficiency, high yield and suitability for industrial mass production.
Description
Technical Field
The invention relates to the technical field of medicine synthesis and preparation, and particularly relates to a preparation method of an S-configuration phenethylamine hydrochloride compound.
Background
Hepatitis B Virus (HBV) is a enveloped, partially double-stranded DNA (dsdna), virus of the Hepadnaviridae family (Hepadnaviridae). Its genome comprises 4 overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode the three enveloped capsulins), and the X gene. Before infection, the partially double-stranded DNA genome is converted in the host cell nucleus (open circular DNA, rcDNA) into covalently closed circular DNA (cccdna) and the viral mRNA is transcribed. Once chitonized, the pregenomic RNA (pgRNA), which also encodes the core egg mortar and Pol, serves as a template for reverse transcription that regenerates the portion of the dsDNA genome (rcDNA) in the nucleocapsid
HBV causes epidemics in parts of asia and africa, and it is endemic in china. HBV has infected approximately 20 million people worldwide, of which approximately 3.5 million develop into chronic infectious diseases. The virus causes hepatitis b disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
Transmission sources of hepatitis b virus expose thousand infectious blood or body fluids, while viral DNA is detected in saliva, tears, and urine of chronic carriers with high titers of DNA in serum. Although there is currently an effective and well-tolerated vaccine, the choice of direct therapy is currently limited to interferon and the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.
However, there are problems in these direct HBV antiviral agents such as toxicity, mutagenicity, lack of selectivity, poor therapeutic effect, poor bioavailability and difficulty in synthesis.
Patent CN110437132A discloses a highly potent and less toxic HBV inhibitor, wherein the related compound relates to a key intermediate E1, a single chiral phenethylamine hydrochloride, as shown below:
the published synthesis method can be seen in Tetrahedron Asymmetry,2014, vol.25, #5, p.435-442, which reports 2 methods for synthesizing compound E1 from compound 1.
A compound 2 is prepared by reacting a compound 1 with formic acid and ammonia gas, the compound 2 is refluxed in a sodium hydroxide solution to obtain a racemate rac-2, and the racemate rac-2 is split by chiral acid in an attempt, and the specific synthetic route is as follows:
in the above method, the yield in the first two steps is only 21%, and the ee after three times of crystallization is only 14% at most, which is difficult to satisfy the quality requirement of the medicine.
The second method is to synthesize the compound E1 by using acetone as a cosolvent and an enzyme catalysis method through racemate rac-2; the specific synthetic route is as follows:
four reported enzymes are reported in the literature to be tried, the only effective enzyme is Novozym 435, the yield can reach 49%, and the ee% can reach more than 99%, but the enzyme is expensive, has single adaptability to substrates, has narrow requirements on pH and temperature in the reaction process, and has very high requirements on equipment in large-scale industrial production.
The synthesis of compound 1 is described in the documents N.Al-Maharik, N.P.keying/Tetrahedron 60 (2004) 1637-1642 and Synthetic Communications1,44: 540-546, 2014.
In the text, 1, 3-dimethoxybenzene is used and reacted by taking nitroethane or dichloromethane as a solvent in the presence of acetyl chloride and aluminum trichloride, and the specific route is as follows:
nitroethane solvent has a great safety risk, and dichloromethane is highly safe, but the whole cost also has a great promotion space.
In order to solve the problems, the synthetic method of the single chiral phenethylamine hydrochloride is simple, efficient, low in cost, high in yield and suitable for industrial mass production.
Disclosure of Invention
The invention provides a preparation method of an S-configuration phenethylamine hydrochloride compound, which has the advantages of low cost, high yield and simple operation and is suitable for industrial production.
The invention aims to solve the problems existing in the prior art and provide a preparation method of an S-configuration phenethylamine hydrochloride compound.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of S-configuration phenethylamine hydrochloride compound,
the structure of the compound is:
r1 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy;
r2 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy;
the preparation method comprises the following preparation steps:
(1) synthesis of intermediate a: 1, 3-disubstituted benzene is subjected to acetyl chloride to obtain an intermediate A in aluminum trichloride, and the intermediate A is not separately separated;
(2) synthesis of intermediate B: reacting the intermediate A obtained in the step (1) under the condition that hydroxylamine hydrochloride and triethylamine participate to obtain an intermediate B;
(3) and (3) synthesizing an intermediate C: obtaining a compound C from the intermediate B obtained in the step (2) under the action of a reducing agent;
(4) single chiral resolution: resolving the intermediate C obtained in the step (3) and single chiral acid in an organic solvent to form salt so as to obtain organic salt of a compound D with S configuration;
(5) synthesis of Compound E: reacting the intermediate C obtained in the step (4) with sodium hydroxide and hydrogen chloride gas in an organic solvent to generate a compound E;
the general reaction formula of the steps is as follows:
as a further improvement of the present solution, the specific operation in step (1) is: dissolving 1, 3-disubstituted benzene and aluminum trichloride in an anhydrous organic solvent 1, adding acetyl chloride at the temperature of-20-30 ℃, reacting at the temperature of-20-40 ℃ for 1-5h, quenching with water, concentrating to dryness to obtain an intermediate A, wherein the intermediate A does not need to be purified independently, and is prepared into a reaction solution in the next step for direct use;
the specific operation of the step (2) is as follows: adding the intermediate A into an organic solvent 2, triethylamine and hydroxylamine hydrochloride, heating to 40-80 ℃, continuing to react for 3-8h, then adding water, filtering and drying to obtain an intermediate B;
the specific operation of the step (3) is as follows: adding the intermediate B into an organic solvent 3, adding a reducing agent and a catalyst, controlling the system temperature at 0-60 ℃, reacting for 3-25h at the temperature, then cooling to room temperature, filtering, collecting filtrate, concentrating and drying the filtrate to obtain an intermediate C; the molar ratio of the intermediate B, the reducing agent and the catalyst is 1:0.01-5: 0.01-1.0;
the specific operation of the step (4) is as follows: adding an intermediate C into an organic solvent 3 for dissolution, adding a single chiral organic acid into an organic solvent 4 for dissolution, dropwise adding an organic acid solution into the intermediate C solution at room temperature, stirring at room temperature for 1 hour, separating out a large amount of solids, filtering, recrystallizing and drying to obtain an organic salt of an intermediate D, wherein the molar ratio of the intermediate C to the single chiral organic acid is 1: 0.3-1.0;
the specific operation of the step (5) is as follows: adding an intermediate D organic acid into dichloromethane, adding a 10% sodium hydroxide solution, stirring at room temperature for 30 minutes, concentrating a dichloromethane phase to dryness after liquid separation, adding an organic solvent 5 for dissolution, continuously introducing dry hydrogen chloride gas into the solution for 30 minutes to separate out a large amount of solids, filtering and drying to obtain a target compound, namely single chiral phenethylamine hydrochloride, wherein the molar ratio of the intermediate D organic acid to the sodium hydroxide is 1: 1.0-2.0.
As a further improvement of the scheme, the organic solvent 1 is any one of anhydrous dichloromethane and anhydrous 1, 2-dichloroethane.
As a further improvement of the scheme, in the step (1), the molar ratio of the 1, 3-disubstituted benzene, the aluminum trichloride and the acetyl chloride is as follows: 1.0:0.9-2:0.9-2.0.
As a further improvement of the scheme, in the step (2), the molar ratio of the intermediate A, triethylamine and hydroxylamine hydrochloride is as follows: 1.0:0.9-2.0:0.9-2.0.
As a further improvement of this embodiment, in step (2), the organic solvent 2 is any one of methanol, ethanol, isopropanol, and tetrahydrofuran.
As a further improvement of this embodiment, in step (3), the organic solvent 3 is any one of methanol, ethanol, isopropanol, tetrahydrofuran, and 1, 4-dioxane; the reducing agent is any one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and sodium triacetoxyborohydride; the catalyst is any one of iodine, raney nickel, palladium carbon and platinum carbon.
As a further improvement of this embodiment, the single chiral organic acid in step (4): any one of D-mandelic acid, D-tartaric acid, L-aspartic acid and L-malic acid; the organic solvent 4 is: any one of isopropanol, ethanol, methanol, acetone, and ethyl acetate.
As a further improvement of the scheme, in the step (5), the organic solvent 5 is: ethyl acetate, isopropyl acetate, 1, 4-dioxane, isopropanol, ethanol, and dichloromethane.
The preparation method of the S-configuration phenethylamine hydrochloride compound has the advantages that: the method comprises the following steps of taking low-cost commercial basic chemical raw material 1, 3-disubstituted benzene as an initial raw material, and carrying out five-step reaction to obtain a target product compound E, wherein the method specifically comprises the following steps: the method has the advantages of no separation of intermediate state, no need of Friedel-crafts, oxime formation, reduction, resolution and salification to obtain the single chiral phenylethylamine hydrochloride, no need of using starting raw materials which are high in cost and difficult to obtain, great reduction of the synthesis cost of the target product compound E, simple purification, low cost, high efficiency, high yield and suitability for industrial mass production, and provides a new synthesis route.
Drawings
FIG. 1 shows an embodiment 1 of the present invention
FIG. 2 is an HPLC (RPLC) profile of example 1 of the present invention;
FIG. 3 is an HPLC (NPLC) profile of example 2 of the present invention;
FIG. 4 shows example 2 of the present invention
FIG. 5 shows example 3 of the present invention
FIG. 6 shows example 3 of the present invention
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:
the present invention will be described in detail with reference to the following examples:
the preparation method of the single chiral phenethylamine hydrochloride compound is characterized by comprising the following steps: the preparation method of the single chiral phenethylamine hydrochloride compound is characterized by comprising the following steps: the structure of the compound is:
r1 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy (the same applies below)
R2 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy (the same applies below)
The method comprises the following synthetic steps: it comprises the following steps:
(1) synthesis of intermediate a: 1, 3-disubstituted benzene is subjected to acetyl chloride to obtain an intermediate A in aluminum trichloride, wherein the intermediate A is not separately separated, and the structure of the intermediate A is as follows:
(2) synthesis of intermediate B: reacting the intermediate A obtained in the step (1) under the condition that hydroxylamine hydrochloride and triethylamine participate to obtain an intermediate B; wherein the structure of the intermediate B is as follows:
(3) and (3) synthesizing an intermediate C: reducing the intermediate B obtained in the step (2) in the presence of a reducing agent to obtain an organic salt of a compound C; wherein, the structure of the compound C is as follows:
(4) single chiral resolution: resolving the intermediate C obtained in the step (2) and single chiral acid in an organic solvent to form salt so as to obtain organic salt of a compound D with S configuration; wherein the organic salt structure of compound C is:
(5) synthesis of Compound E: reacting the intermediate C obtained in the step (3) with sodium hydroxide and hydrogen chloride gas in an organic solvent to generate a compound E; wherein, the structure of the compound E is as follows:
wherein the specific operation in the step (1) is as follows: dissolving 1, 3-disubstituted benzene and aluminum trichloride in an anhydrous organic solvent 1, adding acetyl chloride at the temperature of-20-30 ℃, reacting at the temperature of-20-40 ℃ for 1-5h, quenching with water, concentrating to dryness to obtain an intermediate A, wherein the intermediate A does not need to be purified independently, and is prepared into a reaction solution in the next step for direct use.
The organic solvent 1 is one of anhydrous dichloromethane and anhydrous 1, 2-dichloroethane, and dichloromethane is preferred.
Wherein the molar ratio of the 1, 3-disubstituted benzene to the aluminum trichloride to the acetyl chloride is as follows: 1.0:0.9-2:0.9-2.0, preferably 1:1.0: 1.0.
The specific operation in the step (2) is as follows: adding the intermediate A into an organic solvent 2, triethylamine and hydroxylamine hydrochloride, heating to 40-80 ℃, continuing to react for 3-8h, then adding water, filtering and drying to obtain an intermediate B;
wherein the molar ratio of the intermediate A to the triethylamine to the hydroxylamine hydrochloride is as follows: 1.0:0.9-2.0:0.9-2.0, preferably 1.0:1.5: 1.5.
The organic solvent 2 is one of methanol, ethanol, isopropanol and tetrahydrofuran, and ethanol is preferred.
The specific operation of the step (3) is as follows: adding the intermediate B into an organic solvent 2, adding a reducing agent and a catalyst, controlling the system temperature at 0-60 ℃, reacting for 3-25h at the temperature, then cooling to room temperature, filtering, collecting filtrate, concentrating and drying the filtrate to obtain an intermediate C; the molar ratio of the intermediate B, the reducing agent and the catalyst is 1:0.01-5:0.01-1.0, preferably 1.0:5: 0.03.
The organic solvent 2 is: one of methanol, ethanol and tetrahydrofuran, preferably methanol.
The reducing agent is: one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and sodium triacetoxyborohydride, and hydrogen is preferred.
The catalyst is as follows: one of iodine, Raney nickel, palladium carbon and platinum carbon, preferably Raney nickel.
The specific operation of the step (4) is as follows: adding an intermediate C into an organic solvent 3 for dissolution, adding a single chiral organic acid into an organic solvent 4 for dissolution, dropwise adding an organic acid solution into the intermediate C solution at room temperature, stirring at room temperature for 1 hour, precipitating a large amount of solids, filtering, recrystallizing and drying to obtain an organic salt of an intermediate D, wherein the molar ratio of the intermediate C to the single chiral organic acid is 1:0.3-1.0, preferably 1:0.5
The organic solvent 3 is: one of ethyl acetate, acetone and tetrahydrofuran, preferably ethyl acetate.
The single chiral organic acid: one of D-mandelic acid, D-tartaric acid, L-aspartic acid and L-malic acid, preferably D-mandelic acid.
The organic solvent 4 is: one of isopropanol, ethanol, methanol, acetone and ethyl acetate, preferably isopropanol.
The specific operation of the step (5) is as follows: adding an intermediate D organic acid into dichloromethane, adding a 10% sodium hydroxide solution, stirring at room temperature for 30 minutes, concentrating a dichloromethane phase to dryness after liquid separation, adding an organic solvent 5 for dissolution, continuously introducing dry hydrogen chloride gas into the solution for 30 minutes to separate out a large amount of solids, filtering and drying to obtain a target compound, namely single chiral phenethylamine hydrochloride, wherein the molar ratio of the intermediate D organic acid to the sodium hydroxide is 1:1.0-2.0, preferably 1:1.5
The organic solvent 5 is: one of ethyl acetate, isopropyl acetate, 1, 4-dioxane, isopropanol, ethanol and dichloromethane, preferably isopropyl acetate.
Example 1
Adding m-phenyl dimethyl ether (100g), dichloromethane (665g) and aluminum trichloride (96.5g) into a 1L reaction bottle, dropwise adding acetyl chloride (56.8g) at 5 ℃, preserving heat for 1 hour at 25 ℃ after dropwise adding, adding water (500g) after finishing the reaction, quenching the reaction, concentrating an organic phase to be dry after liquid separation, adding ethanol (300g), triethylamine (110g) and hydroxylamine hydrochloride (76.0g), dropwise adding water (783g) after preserving heat for 3 hours at 45 ℃, separating out a large amount of solids, cooling to room temperature, filtering, and drying to obtain an intermediate B109 g, wherein the yield is 78%;
an intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81(d, J ═ 8.7Hz,1H),6.50 (dd, J ═ 8.7,2.3Hz,1H),6.44(d, J ═ 2.3Hz,1H),3.87(s,3H),3.83(d, J ═ 0.9Hz,3H), 2.56(d, J ═ 0.9Hz,3H).
An intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85(s,1H),7.13(d, J ═ 8.3Hz, 1H),6.59(d, J ═ 2.3Hz,1H),6.50(dd, J ═ 8.4,2.4Hz,1H),3.78(s,3H), 2.02(s,3H).
Adding the intermediate B (100g), methanol (792g) and Raney nickel (3.3g) into a 2L high-pressure reaction kettle, pressurizing with hydrogen at 60 ℃ under 0.8Mpa, reacting for 5h, cooling to room temperature, filtering, collecting filtrate, concentrating the filtrate, adding dichloromethane, washing with hydrochloric acid solution and sodium hydroxide solution, and concentrating to obtain 56g of light yellow oily matter with the yield of 61%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4 Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H)。
adding an intermediate C (40g) and ethyl acetate (140g) into a 500mL reaction bottle, heating to 50 ℃, stirring for dissolving, adding R-mandelic acid (16.8g) into isopropanol (48g), heating to 40 ℃, dissolving, dropwise adding the R-mandelic acid solution into the intermediate C solution, naturally cooling to room temperature after dropwise adding, stirring for 1 hour, filtering, recrystallizing with ethyl acetate and ethanol, filtering, and drying to obtain an intermediate D mandelate, wherein the yield of a white solid is 25% ee%: 99.1 percent;
after adding intermediate D (18g), dichloromethane (36g) and 10% sodium hydroxide solution (36g) to a 100mL reaction flask, stirring at room temperature for 20 minutes, separating the solution, concentrating dichloromethane, adding isopropyl acetate (25.9g), introducing dry hydrogen chloride gas into the solution for 15 minutes, precipitating a large amount of solid, filtering, and drying to obtain a pale yellow solid 10.98g, yield 93%, HPLC purity: 99.9%, ee%: 99.1 percent.
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64– 6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz, 3H)。
The HPLC (RPLC) profile is shown in FIG. 1:
HPLC (NPLC) profile is shown in FIG. 2:
| retention time | Configuration(s) |
| RT15.27min | S configuration |
| RT18.38min | R configuration |
Example 2
Adding 100g of m-phenyl dimethyl ether, 56.8g of 1, 2-dichloroethane and 96.5g of aluminum trichloride into a 1L reaction bottle, dropwise adding acetyl chloride at 5 ℃, keeping the temperature at 25 ℃ for 1 hour after dropwise adding, adding 500g of water to quench the reaction after the reaction is finished, concentrating an organic phase to be dry after liquid separation, adding 200g of methanol, 110g of triethylamine and 76.0g of hydroxylamine hydrochloride, keeping the temperature at 45 ℃ for 3 hours, dropwise adding 783g of water, precipitating a large amount of solid, cooling to room temperature, filtering and drying to obtain 91.83g of an intermediate B, wherein the yield is 65%;
an intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81(d, J ═ 8.7Hz,1H),6.50 (dd, J ═ 8.7,2.3Hz,1H),6.44(d, J ═ 2.3Hz,1H),3.87(s,3H),3.83(d, J ═ 0.9Hz,3H), 2.56(d, J ═ 0.9Hz,3H).
An intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85(s,1H),7.13(d, J ═ 8.3Hz, 1H),6.59(d, J ═ 2.3Hz,1H),6.50(dd, J ═ 8.4,2.4Hz,1H),3.78(s,3H), 2.02(s,3H).
Adding an intermediate B (90g) and tetrahydrofuran (783g) into a 5L reaction bottle, dissolving, adding sodium borohydride (52.3g), cooling to 0 ℃, mixing iodine (58.5g) and tetrahydrofuran (292.5g), dropwise adding the mixture into the intermediate B solution at 0 ℃, reacting at 60 ℃ for 8 hours after dropwise adding is completed, cooling to room temperature, filtering, collecting filtrate, concentrating the filtrate, adding dichloromethane, washing with a hydrochloric acid solution, washing with a sodium hydroxide solution, and concentrating to obtain 43.2g of a light yellow oily substance, wherein the yield is 51%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4 Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H).
adding the intermediate C (40g) and acetone (120g) into a 500mL reaction bottle, heating to 50 ℃, stirring for dissolving, adding L-aspartic acid (14.6g) into methanol (43.8g), heating to 50 ℃ for dissolving, dropwise adding an aspartic acid solution into the intermediate C solution, naturally cooling to room temperature, stirring for 1 hour, filtering, and drying to obtain an intermediate D aspartate, 14.56g of a white solid, wherein the yield is 21.0%, and ee%: 93.2 percent;
a 1000mL reaction flask was charged with intermediate D (14g), dichloromethane (28g), and 10% sodium hydroxide solution (28g), stirred at room temperature for 20 minutes, separated, and after dichloromethane was concentrated, ethyl acetate (14g) was added, and then dry hydrogen chloride gas was introduced into the solution for 15 minutes, whereby a large amount of solid precipitated, and the mixture was filtered and dried to obtain 8.66g of a pale yellow solid, which was 89.4% in yield and% ee: 93.2 percent
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64– 6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz, 3H).
The HPLC (RPLC) profile is shown in FIG. 3:
HPLC (NPLC) profile is shown in FIG. 4:
| retention time | Configuration(s) |
| RT15.21min | S configuration |
| RT18.38min | R configuration |
Example 3
Adding m-phenyl dimethyl ether (100g), dichloromethane (665g) and aluminum trichloride (96.5g) into a 1L reaction bottle, dropwise adding acetyl chloride (56.8g) at 5 ℃, preserving heat for 1 hour at 25 ℃ after dropwise adding, adding water (500g) after finishing the reaction, quenching the reaction, concentrating an organic phase to be dry after liquid separation, adding tetrahydrofuran (261g), triethylamine (110g) and hydroxylamine hydrochloride (76.0g), preserving heat for 3 hours at 45 ℃, dropwise adding water (783g), precipitating a large amount of solids, cooling to room temperature, filtering, and drying to obtain an intermediate B100.3 g, wherein the yield is 75.0%;
an intermediate A: 1H NMR (400MHz, Chloroform-d) δ 7.81(d, J ═ 8.7Hz,1H),6.50 (dd, J ═ 8.7,2.3Hz,1H),6.44(d, J ═ 2.3Hz,1H),3.87(s,3H),3.83(d, J ═ 0.9Hz,3H), 2.56(d, J ═ 0.9Hz,3H).
An intermediate B: 1H NMR (400MHz, DMSO-d6) δ 10.85(s,1H),7.13(d, J ═ 8.3Hz, 1H),6.59(d, J ═ 2.3Hz,1H),6.50(dd, J ═ 8.4,2.4Hz,1H),3.78(s,3H), 2.02(s,3H).
Adding the intermediate B (100g), ethanol (790g) and 10% palladium carbon (15g) into a 2L high-pressure reaction kettle, pressurizing by hydrogen at 60 ℃ and 1.0Mpa, reacting for 12 hours, cooling to room temperature, filtering, collecting filtrate, concentrating the filtrate, adding dichloromethane, washing by hydrochloric acid solution and sodium hydroxide solution, and concentrating to obtain 52.4g of light yellow oily matter with the yield of 56.4%;
1H NMR(400MHz,Chloroform-d)δ7.24–7.18(m,1H),6.45(dd,J＝6.5,2.4 Hz,2H),4.28(q,J＝6.7Hz,1H),3.80(s,3H),3.78(s,3H),1.37(d,J＝6.7Hz,3H).
adding the intermediate C (40g) and tetrahydrofuran (107g) into a 500mL reaction bottle, stirring at room temperature for dissolving, adding ethanol (33g) into D-tartaric acid (16.5g) for heating to 40 ℃ for dissolving, dropwise adding the D-tartaric acid solution into the intermediate C solution, naturally cooling to room temperature after dropwise adding, stirring for 1 hour, filtering and drying to obtain tartrate of the intermediate D, 17.1g of white solid, wherein the yield is 23.4%, and ee%: 95.5 percent;
after adding intermediate D (17g), dichloromethane (34g), and 10% sodium hydroxide solution (34g) to a 1000mL reaction flask, stirring at room temperature for 20 minutes, separating the liquids, concentrating dichloromethane, adding 1, 4-dioxane (20.7g), introducing dry hydrogen chloride gas into the solution for 15 minutes, to precipitate a large amount of solid, filtering, and drying to obtain 10.5g of pale yellow solid, yield 93.3%, ee%: 95.5 percent.
1H NMR(400MHz,DMSO-d6)δ8.38(s,3H),7.39(d,J＝8.4Hz,1H),6.64– 6.55(m,2H),4.48(p,J＝6.2Hz,1H),3.82(s,3H),3.77(s,3H),1.46(d,J＝6.8Hz, 3H)。
The HPLC (RPLC) profile is shown in FIG. 5:
HPLC (NPLC) profile is shown in FIG. 6:
| retention time | Configuration(s) |
| RT15.27min | S configuration |
| RT18.38min | R configuration |
The above description is only for the preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention are within the scope of the present invention.
Claims (9)
1. A preparation method of S-configuration phenethylamine hydrochloride compound is characterized in that,
the structure of the compound is:
r1 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy;
r2 is one of methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy and cyclopropyloxy;
the preparation method comprises the following preparation steps:
(1) synthesis of intermediate a: 1, 3-disubstituted benzene is subjected to acetyl chloride to obtain an intermediate A in aluminum trichloride, and the intermediate A is not separately separated;
(2) synthesis of intermediate B: reacting the intermediate A obtained in the step (1) under the condition that hydroxylamine hydrochloride and triethylamine participate to obtain an intermediate B;
(3) and (3) synthesizing an intermediate C: obtaining a compound C from the intermediate B obtained in the step (2) under the action of a reducing agent;
(4) single chiral resolution: resolving the intermediate C obtained in the step (3) and single chiral acid in an organic solvent to form salt so as to obtain organic salt of a compound D with S configuration;
(5) synthesis of Compound E: reacting the intermediate C obtained in the step (4) with sodium hydroxide and hydrogen chloride gas in an organic solvent to generate a compound E;
the general reaction formula of the steps is as follows:
2. the method for preparing S-configuration phenethylamine hydrochloride compound according to claim 1, wherein the specific operation in the step (1) is: dissolving 1, 3-disubstituted benzene and aluminum trichloride in an anhydrous organic solvent 1, adding acetyl chloride at the temperature of-20-30 ℃, reacting at the temperature of-20-40 ℃ for 1-5h, quenching with water, concentrating to dryness to obtain an intermediate A, wherein the intermediate A does not need to be purified independently, and is prepared into a reaction solution in the next step for direct use;
the specific operation of the step (2) is as follows: adding the intermediate A into an organic solvent 2, triethylamine and hydroxylamine hydrochloride, heating to 40-80 ℃, continuing to react for 3-8h, then adding water, filtering and drying to obtain an intermediate B;
the specific operation of the step (3) is as follows: adding the intermediate B into an organic solvent 3, adding a reducing agent and a catalyst, controlling the system temperature at 0-60 ℃, reacting for 3-25h at the temperature, then cooling to room temperature, filtering, collecting filtrate, concentrating and drying the filtrate to obtain an intermediate C; the molar ratio of the intermediate B, the reducing agent and the catalyst is 1:0.01-5: 0.01-1.0;
the specific operation of the step (4) is as follows: adding an intermediate C into an organic solvent 3 for dissolution, adding a single chiral organic acid into an organic solvent 4 for dissolution, dropwise adding an organic acid solution into the intermediate C solution at room temperature, stirring at room temperature for 1 hour, separating out a large amount of solids, filtering, recrystallizing and drying to obtain an organic salt of an intermediate D, wherein the molar ratio of the intermediate C to the single chiral organic acid is 1: 0.3-1.0;
the specific operation of the step (5) is as follows: adding an intermediate D organic acid into dichloromethane, adding a 10% sodium hydroxide solution, stirring at room temperature for 30 minutes, concentrating a dichloromethane phase to dryness after liquid separation, adding an organic solvent 5 for dissolution, continuously introducing dry hydrogen chloride gas into the solution for 30 minutes to separate out a large amount of solids, filtering and drying to obtain a target compound, namely single chiral phenethylamine hydrochloride, wherein the molar ratio of the intermediate D organic acid to the sodium hydroxide is 1: 1.0-2.0.
3. The method for preparing S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the organic solvent 1 is any one of anhydrous dichloromethane and anhydrous 1, 2-dichloroethane.
4. The method for preparing S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the molar ratio of the 1, 3-disubstituted benzene, aluminum trichloride and acetyl chloride in the step (1) is as follows: 1.0:0.9-2:0.9-2.0.
5. The method for preparing S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the molar ratio of the intermediate A, triethylamine and hydroxylamine hydrochloride in the step (2) is as follows: 1.0:0.9-2.0:0.9-2.0.
6. The method for preparing an S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the organic solvent 2 in the step (2) is any one of methanol, ethanol, isopropanol and tetrahydrofuran.
7. The method for preparing an S-configuration phenethylamine hydrochloride compound according to claim 2, wherein in the step (3), the organic solvent 3 is any one of methanol, ethanol, isopropanol, tetrahydrofuran and 1, 4-dioxane; the reducing agent is any one of hydrogen, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and sodium triacetoxyborohydride; the catalyst is any one of iodine, raney nickel, palladium carbon and platinum carbon.
8. The method for preparing an S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the single chiral organic acid: any one of D-mandelic acid, D-tartaric acid, L-aspartic acid and L-malic acid; the organic solvent 4 is: any one of isopropanol, ethanol, methanol, acetone, and ethyl acetate.
9. The method for preparing an S-configuration phenethylamine hydrochloride compound according to claim 2, wherein the organic solvent 5 in the step (5) is: ethyl acetate, isopropyl acetate, 1, 4-dioxane, isopropanol, ethanol, and dichloromethane.
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