CN113527114A - Preparation method of tomoxetine hydrochloride - Google Patents
Preparation method of tomoxetine hydrochloride Download PDFInfo
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- CN113527114A CN113527114A CN202110658073.XA CN202110658073A CN113527114A CN 113527114 A CN113527114 A CN 113527114A CN 202110658073 A CN202110658073 A CN 202110658073A CN 113527114 A CN113527114 A CN 113527114A
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- 229960002430 atomoxetine Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- VHGCDTVCOLNTBX-QGZVFWFLSA-N atomoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C VHGCDTVCOLNTBX-QGZVFWFLSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006467 substitution reaction Methods 0.000 claims abstract description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 36
- 238000003756 stirring Methods 0.000 claims description 36
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims description 34
- 150000001875 compounds Chemical class 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 239000012279 sodium borohydride Substances 0.000 claims description 24
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 24
- LUCXVPAZUDVVBT-UNTBIKODSA-N atomoxetine hydrochloride Chemical compound Cl.O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C LUCXVPAZUDVVBT-UNTBIKODSA-N 0.000 claims description 23
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 18
- 239000012065 filter cake Substances 0.000 claims description 18
- 238000000967 suction filtration Methods 0.000 claims description 18
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 claims description 17
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims description 17
- 238000001035 drying Methods 0.000 claims description 17
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 16
- MMZYCBHLNZVROM-UHFFFAOYSA-N 1-fluoro-2-methylbenzene Chemical compound CC1=CC=CC=C1F MMZYCBHLNZVROM-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 10
- 229960002828 atomoxetine hydrochloride Drugs 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 8
- 239000007789 gas Substances 0.000 claims description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 8
- 229910015844 BCl3 Inorganic materials 0.000 claims description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 6
- 238000007664 blowing Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 235000019441 ethanol Nutrition 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 238000012544 monitoring process Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 235000006408 oxalic acid Nutrition 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- -1 (R) -N-methyl-3- (2-methylphenoxy) -3-phenylalanyl Chemical group 0.000 abstract description 3
- NIOHSOXYJMSVOA-UHFFFAOYSA-N 1-chloro-3-phenylpropan-2-one Chemical compound ClCC(=O)CC1=CC=CC=C1 NIOHSOXYJMSVOA-UHFFFAOYSA-N 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 150000001412 amines Chemical class 0.000 abstract description 2
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 17
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 3
- JZFUHAGLMZWKTF-VIFPVBQESA-N (1s)-3-chloro-1-phenylpropan-1-ol Chemical compound ClCC[C@H](O)C1=CC=CC=C1 JZFUHAGLMZWKTF-VIFPVBQESA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229950009195 phenylpropanol Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940012488 strattera Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of tomoxetine hydrochloride, which belongs to the technical field of drug synthesis, and is characterized in that 3-chloro-1-phenyl acetone is used as a raw material, and the (R) -N-methyl-3- (2-methylphenoxy) -3-phenylalanyl amine hydrochloride is prepared through reduction reaction, substitution reaction, methylamination reaction and salification reaction.
Description
Technical Field
The invention relates to the technical field of drug synthesis, and particularly relates to a preparation method of tomoxetine hydrochloride.
Background
Atomoxetine hydrochloride, chemical name: (R) -N-methyl-3- (2-methylphenoxy) -3-phenylalanyl amine hydrochloride, trade name: STRATTERA are provided. Developed by bayer pharmaceutical company, approved by fda (food and drug administration) in the united states for marketing in 11 months 2002, and is suitable for the treatment of patients with childhood hyperkinetic syndrome (ADHD) 6 years old and older; approved by the European drug administration (EMA) to be marketed in 2004 for the treatment of childhood hyperkinetic syndrome.
Atomoxetine hydrochloride, the (R) - (-) enantiomer of atomoxetine, is a selective norepinephrine reuptake inhibitor having the formula:
the synthesis route of atomoxetine hydrochloride is various, for example, the synthesis route is that diisopinocampheyl boron chloride is used as a catalyst to selectively reduce 3-chloro-1-phenyl ketone to obtain (S) - (-) -3-chloro-1-phenyl propanol. Then (S) - (-) -3-chloro-1-phenyl propanol is subjected to Mitsunobu reaction to obtain ether, and then subjected to methylamine reaction and salification to obtain the product.
The method has the advantages of few reaction steps and good stereoselectivity, but the cost of the selective catalyst is high.
Such as phenylpropanol, through chlorination, bromination, etherification, methylamine, resolution and salification.
The method uses mandelic acid for resolution, and then acidification is carried out to form hydrochloride, and finally R- (-) -tomoxetine hydrochloride is generated. Although the reaction conditions are mild, the method has many reaction steps and is not beneficial to industrial production.
Disclosure of Invention
The invention provides a preparation method of tomoxetine hydrochloride, and the synthetic route has the advantages of few reaction steps, mild reaction conditions and easy industrial production.
In order to achieve the technical purpose, the technical scheme of the invention is realized as follows:
a preparation method of tomoxetine hydrochloride comprises the following steps:
(1) selectively reducing the compound I to generate a compound II;
(2) carrying out substitution reaction on the compound II and o-fluorotoluene to generate a compound III;
(3) carrying out a methylamination reaction on the compound III to generate a compound IV;
(4) and salifying the compound IV with hydrogen chloride gas in an organic solvent to obtain the tomoxetine hydrochloride.
Wherein, the step (1) is specifically as follows: taking NaBH4Adding into round bottom flask, introducing nitrogen, adding dimethoxyethane and alpha-pinene, stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3Aging at room temperature for 2 hours to obtain a compound I; adding isopropyl ether into a three-necked bottle at room temperature, stirring uniformly, dropwise adding the compound I, reacting for two hours at 20-30 ℃, extracting the reaction liquid with absolute ethyl alcohol, washing with saturated saline solution until the pH value reaches 8.0, and drying to obtain a compound II.
Wherein the optical purity of the alpha-pinene is more than or equal to 70 percent.
Wherein, the NaBH4The mol ratio of alpha-pinene is 1: 3-5, said NaBH4And BCl3In a molar ratio of 1: 1-1.2, said NaBH4The molar ratio to compound I is: 1: 1-1.25.
Wherein the step (2) specifically comprises: adding dimethyl sulfoxide into a three-neck flask, adding a compound II, stirring and dissolving, heating to 80-90 ℃, dropwise adding o-fluorotoluene, monitoring by TLC for complete reaction, cooling to room temperature, adding ethyl acetate and water, fully stirring to separate an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and performing reduced pressure drying on the filter cake at 40-50 ℃ to obtain a compound III.
Wherein the molar ratio of the compound II to the o-fluorotoluene is 1: 1-1.3.
Refluxing a compound III to an ethanol solution of methylamine for 3-4 hours to obtain a compound IV, wherein the molar ratio of the compound III to the methylamine is 1: 1.1-1.3.
Wherein the step (4) is specifically as follows: adding the compound IV into a three-neck flask, adding acetone, stirring for dissolving, controlling the temperature of the system to be 60-70 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to be 1-2, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing at 50 ℃ to obtain a compound V.
The invention has the beneficial effects that:
the (R) -N-methyl-3- (2-methylphenoxy) -3-phenylalkylamine hydrochloride is prepared by taking 3-chloro-1-phenyl acetone as a raw material through reduction reaction, substitution reaction, methylamination reaction and salification reaction, the synthetic route has few reaction steps, mild reaction conditions and simple operation, and the 3-chloro-1-phenyl acetone is taken as the raw material, so that the raw material is cheap and easy to obtain, and the production cost is low.
Detailed Description
The technical solutions of the present invention are clearly and completely described below by using specific embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The embodiment provides a preparation method of tomoxetine hydrochloride, which comprises the following steps:
(1) taking NaBH4(50g) Adding into a round-bottom flask, introducing nitrogen, adding dimethoxyethane 2000ml and alpha-pinene (720.2g), stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3(170.4g) and aging at room temperature for 2 hours to give Compound I (256.3 g); adding isopropyl ether into a three-necked flask at room temperature, stirring, adding compound I dropwise, reacting at 25 deg.C for two hours, extracting the reaction solution with anhydrous ethanol, washing with saturated salt waterWashing the pH value to 8.0, and drying in the air to obtain a compound II (232.5 g), wherein the yield is 90.2%. Wherein the optical purity of the alpha-pinene is 78%. The NaBH4The mol ratio of alpha-pinene is 1: 4, said NaBH4And BCl3In a molar ratio of 1:1.1, said NaBH4The molar ratio to compound I is: 1: 1.15.
(2) adding 1000ml of dimethyl sulfoxide into a three-neck flask, adding a compound II (232.2 g), stirring and dissolving, heating to 85 ℃, dropwise adding o-fluorotoluene (180.9g), monitoring the reaction by TLC to be complete, cooling to room temperature, adding 500ml of ethyl acetate and 300ml of water, fully stirring to separate out an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and drying the filter cake at 45 ℃ under reduced pressure to obtain a compound III (306.0 g), wherein the purity is 80.2%. Wherein the molar ratio of the compound II to the o-fluorotoluene is 1: 1.2.
(3) compound III (305.0g) was refluxed in an ethanol solution of methylamine (containing 40.8g of methylamine) for 3.5 hours to give compound IV (256.5) with a yield of 85.6%. The molar ratio of the compound III to the methylamine is 1: 1.2.
(4) Adding a compound IV (251.1g) into a three-neck flask, adding 1000ml of acetone, stirring for dissolving, controlling the temperature of the system to 65 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to 1.5, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing air at 50 ℃ to obtain a compound V (211.2 g), wherein the purity is 99.2% and the yield is 78.3%.
Example 2
The embodiment provides a preparation method of tomoxetine hydrochloride, which comprises the following steps:
(1) taking NaBH4(50g) Adding into a round-bottom flask, introducing nitrogen, adding dimethoxyethane 2000ml and alpha-pinene (540.2g), stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3(154.9g), and aging at room temperature for 2 hours to give Compound I (222.9 g); adding isopropyl ether into a three-necked bottle at room temperature, stirring uniformly, dropwise adding the compound I, reacting for two hours at 20-30 ℃, extracting the reaction liquid by using absolute ethyl alcohol, washing the reaction liquid by using saturated saline solution until the pH value reaches 8.0, and airing to obtain the compound II (185.6), wherein the yield is 91.8%. Wherein, the alpha-pineneThe optical purity is more than or equal to 70 percent. The NaBH4The mol ratio of alpha-pinene is 1: 3, said NaBH4And BCl3In a molar ratio of 1:1, said NaBH4The molar ratio to compound I is: 1:1.
(2) adding 1000ml of dimethyl sulfoxide into a three-neck flask, adding a compound II (184.9g), stirring and dissolving, heating to 80 ℃, dropwise adding o-fluorotoluene (120.1g), monitoring the reaction by TLC to be complete, cooling to room temperature, adding 500ml of ethyl acetate and 300ml of water, fully stirring to separate out an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and drying the filter cake at 50 ℃ under reduced pressure to obtain a compound III (241.9 g), wherein the purity is 79.6%. Wherein the molar ratio of the compound II to the o-fluorotoluene is 1:1.
(3) compound III (240.0g) was refluxed in an ethanol solution of methylamine (containing 29.5g of methylamine) for 3 hours to give compound IV (19.4.0g) with a yield of 82.3%. The molar ratio of the compound III to the methylamine is 1: 1.1.
(4) Adding a compound IV (192.2g) into a three-neck flask, adding 1000ml of acetone, stirring for dissolving, controlling the temperature of the system to 60 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to be 2, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing at 50 ℃ to obtain a compound V (162.1 g), wherein the purity is 99.3% and the yield is 78.6%.
Example 3
The embodiment provides a preparation method of tomoxetine hydrochloride, which comprises the following steps:
(1) taking NaBH4(50g) Adding into a round-bottom flask, introducing nitrogen, adding dimethoxyethane 2000ml and alpha-pinene (900.3g), stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3(185.9g) and aged at room temperature for 2 hours to give Compound I (278.6 g); adding isopropyl ether into a three-necked flask at room temperature, stirring uniformly, dropwise adding the compound I, reacting for two hours at 20-30 ℃, extracting the reaction liquid by using absolute ethyl alcohol, washing the reaction liquid by using saturated saline solution until the pH value reaches 8.0, and drying the reaction liquid to obtain a compound II (207.9g), wherein the purity is 89.6%. Wherein the optical purity of the alpha-pinene is more than or equal to 70 percent. The NaBH4The mol ratio of alpha-pinene is 1: 5, the NaBH4And BCl3In a molar ratio of 1:1.2, said NaBH4The molar ratio to compound I is: 1: 1.25.
(2) Adding 1000ml of dimethyl sulfoxide into a three-necked bottle, adding a compound II (206.7 g), stirring and dissolving, heating to 90 ℃, dropwise adding o-fluorotoluene (174.5g), monitoring the reaction by TLC to be complete, cooling to room temperature, adding 500ml of ethyl acetate and 300ml of water, fully stirring to separate out an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and drying the filter cake at 40 ℃ under reduced pressure to obtain a compound III (275.8 g), wherein the purity is 81.2%. Wherein the molar ratio of the compound II to the o-fluorotoluene is 1: 1.3.
(3) compound III (275.0g) was refluxed in an ethanol solution of methylamine (containing 39.9g of methylamine) for 4 hours to give compound IV (228.6g) with a yield of 84.6%. The molar ratio of the compound III to the methylamine is 1: 1.3.
(4) Adding a compound IV (225.6 g) into a three-neck flask, adding 1000ml of acetone, stirring for dissolving, controlling the temperature of the system to 70 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to be 1, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing air at 50 ℃ to obtain a compound V (191.5 g) with the purity of 99.4% and the yield of 79.2%.
Example 4
The embodiment provides a preparation method of tomoxetine hydrochloride, which comprises the following steps:
(1) taking NaBH4(50g) Adding into a round-bottom flask, introducing nitrogen, adding dimethoxyethane 300ml and alpha-pinene (630.2g), stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3(173.5g) and aged at room temperature for 2 hours to give Compound I (278.6 g); adding isopropyl ether into a three-necked bottle at room temperature, stirring uniformly, dropwise adding the compound I, reacting at 20-30 ℃ for two hours, extracting the reaction liquid with absolute ethyl alcohol, washing with saturated saline solution until the pH value reaches 8.0, and drying to obtain a compound II (207.9g), wherein the yield is 89.9%. Wherein the optical purity of the alpha-pinene is more than or equal to 70 percent. The NaBH4The mol ratio of alpha-pinene is 1: 3.5, the NaBH4And BCl3In a molar ratio of 1: 1.12, said NaBH4With Compounds IThe molar ratio is as follows: 1: 1.2.
(2) adding 300ml of dimethyl sulfoxide into a three-neck flask, adding a compound II (179.0g), stirring and dissolving, heating to 85 ℃, dropwise adding o-fluorotoluene (127.8g), monitoring the reaction by TLC to be complete, cooling to room temperature, adding 500ml of ethyl acetate and 300ml of water, fully stirring to separate out an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and drying the filter cake at 50 ℃ under reduced pressure to obtain a compound III (238.0 g), wherein the purity is 80.9%. Wherein the molar ratio of the compound II to the o-fluorotoluene is 1: 1.1.
(3) compound III (235.0g) was refluxed in an ethanol solution of methylamine (containing 30.2g of methylamine) for 3 hours to give compound IV (193.7g) with a yield of 83.9%. The molar ratio of the compound III to the methylamine is 1: 1.1-1.3.
(4) Adding the compound IV (190.5g) into a three-neck flask, adding 1000ml of acetone, stirring for dissolving, controlling the temperature of the system to 65 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to be 2, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing at 50 ℃ to obtain a compound V (159.0 g) with the purity of 99.2% and the yield of 77.9%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (8)
1. A preparation method of tomoxetine hydrochloride is characterized by comprising the following steps:
(1) selectively reducing the compound I to generate a compound II;
(2) carrying out substitution reaction on the compound II and o-fluorotoluene to generate a compound III;
(3) carrying out a methylamination reaction on the compound III to generate a compound IV;
(4) and salifying the compound IV with hydrogen chloride gas in an organic solvent to obtain the tomoxetine hydrochloride.
2. The process of claim 1, wherein the atomoxetine hydrochloride is prepared by: the step (1) is specifically as follows: taking NaBH4Adding into round bottom flask, introducing nitrogen, adding dimethoxyethane and alpha-pinene, stirring, mixing, cooling to-10 deg.C, and adding BCl dropwise3Aging at room temperature for 2 hours to obtain a compound I; adding isopropyl ether into a three-necked bottle at room temperature, stirring uniformly, dropwise adding the compound I, reacting for two hours at 20-30 ℃, extracting the reaction liquid with absolute ethyl alcohol, washing with saturated saline solution until the pH value reaches 8.0, and drying to obtain a compound II.
3. The process of claim 2, wherein the atomoxetine hydrochloride is prepared by: the optical purity of the alpha-pinene is more than or equal to 70 percent.
4. The process of claim 2, wherein the atomoxetine hydrochloride is prepared by: the NaBH4The mol ratio of alpha-pinene is 1: 3-5, said NaBH4And BCl3In a molar ratio of 1: 1-1.2, said NaBH4The molar ratio to compound I is: 1: 1-1.25.
5. The process of claim 1, wherein the atomoxetine hydrochloride is prepared by: the step (2) is specifically as follows: adding dimethyl sulfoxide into a three-neck flask, adding a compound II, stirring and dissolving, heating to 80-90 ℃, dropwise adding o-fluorotoluene, monitoring by TLC for complete reaction, cooling to room temperature, adding ethyl acetate and water, fully stirring to separate an organic phase, washing with water, performing suction filtration, collecting filtrate, adding oxalic acid into the filtrate, performing suction filtration to collect a filter cake, and performing reduced pressure drying on the filter cake at 40-50 ℃ to obtain a compound III.
6. The process of claim 5, wherein the reaction is carried out in the presence of a base of tomoxetine hydrochloride: the molar ratio of the compound II to the o-fluorotoluene is 1: 1-1.3.
7. The process of claim 1, wherein the atomoxetine hydrochloride is prepared by: and (3) refluxing the compound III to an ethanol solution of methylamine for 3-4 hours to obtain a compound IV, wherein the molar ratio of the compound III to the methylamine is 1: 1.1-1.3.
8. The process of claim 1, wherein the atomoxetine hydrochloride is prepared by: the step (4) is specifically as follows: adding the compound IV into a three-neck flask, adding acetone, stirring for dissolving, controlling the temperature of the system to be 60-70 ℃, introducing hydrogen chloride gas to adjust the pH value of the system to be 1-2, stirring for crystallization, performing suction filtration, and drying a filter cake by blowing at 50 ℃ to obtain a compound V.
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