CN115677655B - Synthesis method of epinastine intermediate - Google Patents
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- CN115677655B CN115677655B CN202211173669.1A CN202211173669A CN115677655B CN 115677655 B CN115677655 B CN 115677655B CN 202211173669 A CN202211173669 A CN 202211173669A CN 115677655 B CN115677655 B CN 115677655B
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- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 9
- 229960003449 epinastine Drugs 0.000 title claims abstract description 9
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 claims abstract description 10
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims abstract description 10
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940112669 cuprous oxide Drugs 0.000 claims abstract description 10
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims abstract description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims abstract description 9
- VMIRJNDPLCQEHB-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine Chemical compound C1CNCCN1C1=CC=CC2=C1C=CS2 VMIRJNDPLCQEHB-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000001681 protective effect Effects 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- 239000012074 organic phase Substances 0.000 claims description 14
- QPBSEYFVZDMBFW-UHFFFAOYSA-N 4-bromo-1-benzothiophene Chemical compound BrC1=CC=CC2=C1C=CS2 QPBSEYFVZDMBFW-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- XDUUWPNOUUQXBX-UHFFFAOYSA-N 1-(1-benzothiophen-4-yl)piperazine;hydrochloride Chemical compound Cl.C1CNCCN1C1=CC=CC2=C1C=CS2 XDUUWPNOUUQXBX-UHFFFAOYSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 7
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- 238000010189 synthetic method Methods 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 229940093956 potassium carbonate Drugs 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000007788 liquid Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 229930182821 L-proline Natural products 0.000 description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 2
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 229960002429 proline Drugs 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- IRMXPESEXLQKHG-UHFFFAOYSA-N 1-benzothiophen-4-amine Chemical compound NC1=CC=CC2=C1C=CS2 IRMXPESEXLQKHG-UHFFFAOYSA-N 0.000 description 1
- YMDZDFSUDFLGMX-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)ethanamine;hydron;chloride Chemical compound [Cl-].ClCC[NH2+]CCCl YMDZDFSUDFLGMX-UHFFFAOYSA-N 0.000 description 1
- YGYUMNQONHLLNC-UHFFFAOYSA-N 4-chloro-1-benzothiophene Chemical compound ClC1=CC=CC2=C1C=CS2 YGYUMNQONHLLNC-UHFFFAOYSA-N 0.000 description 1
- DPQAKBJISUNJNK-UHFFFAOYSA-N 7-(4-chlorobutoxy)-1h-quinolin-2-one Chemical compound C1=CC(=O)NC2=CC(OCCCCCl)=CC=C21 DPQAKBJISUNJNK-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960001210 brexpiprazole Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- -1 tris-tert-butyltetraphenylphosphonium borate Chemical compound 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical field of medicines, and particularly relates to a synthesis method of an epinastine intermediate, which is characterized in that 4-halogenated benzothiophene, piperazine, L-hydroxyproline, cuprous oxide, carbonate and N-methyl-pyrrolidone are mixed, and the mixture is heated for reaction under a protective atmosphere to obtain the 4-piperazinyl benzothiophene.
Description
Technical Field
The application belongs to the technical field of medicines, and particularly relates to a synthetic method of an epinastine intermediate.
Background
Eppiprazole (brexpiprazole) is a novel antipsychotic drug developed by the combination of danish northkeeping and tsuka pharmaceutical co. Epiprazole is known under the chemical name 7- [4- (4-benzo [ b ] thiophen-4-yl-1-piperazin) butoxy ] -2 (1H) -quinolinone under the trade name Rexulit, CAS registry number 913611-97-9.
The tsukamurelus patent reports a method of synthesis of eppiprazole from the coupling of 7- (4-chlorobutoxy) -2 (1H) -quinolinone and 4- (1-piperazinyl) benzothiophene hydrochloride under alkaline conditions.
Among them, 4-piperazinyl benzothiophene hydrochloride is used as a key intermediate, and there are several synthetic methods as follows.
The synthesis of 4- (1-piperazinyl) benzothiophene hydrochloride in xylene from 4-chlorobenzothiophene, piperazine, palladium (II) acetate, tris-tert-butyltetraphenylphosphonium borate, sodium tert-butoxide has been reported by tsukamuse patent CN103717587 a.
CN104829602a reports that N-Boc-piperazine is obtained by reacting anhydrous piperazine with Boc anhydride in a solvent dichloromethane, and then coupling reaction with 4-bromobenzo [ b ] thiophene in the presence of a ligand BINAP and palladium acetate to obtain a compound of formula (V), c) salifying the compound of formula (V) with hydrochloric acid, preferably concentrated hydrochloric acid, to obtain a compound of formula III.
WO2006112464A1 reports the synthesis of 4-piperazinyl benzothiophene from 4-bromobenzothiophene and anhydrous piperazine in toluene over the ligand BINAP and the catalyst tris (dibenzylidene-BASE acetone) dipalladium, followed by the formation of the salt with concentrated hydrochloric acid to give the 4-piperazinyl benzothiophene hydrochloride, the route is as follows:
chinese patent CN105399736a reports the coupling of 4-aminobenzo [ b ] thiophene with bis (2-chloroethyl) amine hydrochloride under the action of p-toluenesulfonamide, and the basification to prepare 4- (1-piperazinyl) benzothiophene, the synthetic route is as follows:
chinese patent CN 109970705A discloses a method for preparing an intermediate of epipiprazole and epipiprazole using inexpensive copper metal, the reaction route is as follows:
disclosure of Invention
The application aims to provide a synthesis method of an epinastine intermediate, which effectively improves the yield and purity of the epinastine intermediate.
The application relates to a synthesis method of an epinastine intermediate, which comprises the steps of mixing 4-halogenated benzothiophene, piperazine, L-hydroxyproline, cuprous oxide, carbonate and N-methyl-pyrrolidone, and heating for reaction under a protective atmosphere to obtain the 4-piperazinyl benzothiophene. The reaction system of the application is an anhydrous system, piperazine is anhydrous piperazine, carbonate is anhydrous carbonate, and carbonate is preferably potassium carbonate.
Preferably, the 4-halobenzothiophene is 4-bromobenzothiophene.
Preferably, the molar ratio of the 4-halogenated benzothiophene to the piperazine to the cuprous oxide to the L-hydroxyproline to the carbonate is 1:1-20:0.1-0.5:0.5-5:0.5-3; more preferably 1:3 to 5:0.1 to 0.3:1 to 2:1 to 2; most preferably 1:5:0.2:1:1.
Preferably, the weight-volume ratio of the total weight of the 4-halogenated benzothiophene, piperazine, L-hydroxyproline, cuprous oxide and carbonate to the N-methyl-pyrrolidone is 170-180:400.
Preferably, the reaction temperature of the heating reaction is 80 to 150 ℃, more preferably 130 ℃. The reaction time is 1 to 48 hours, preferably 6 to 24 hours, and more preferably 10 hours.
The application provides a synthetic method of an epinastine intermediate, which comprises the steps of diluting 4-piperazinyl benzothiophene with water, extracting with dichloromethane, merging organic phases and concentrating; adding methanol and acetone into the concentrated organic phase, then adding a mixed solution of concentrated acetone hydrochloride, and carrying out suction filtration to obtain the 4-piperazinyl benzothiophene hydrochloride.
The reaction scheme of one embodiment of the present application is as follows:
the application has the beneficial effects that the N-methyl-pyrrolidone is used as the solvent, and compared with the solvents such as N, N-dimethylformamide, dimethyl sulfoxide and the like, the purity and the yield of the product are higher, the yield is 95.3%, and the purity is 99.6%.
Drawings
FIG. 1 is a mass spectrum of 4-piperazinyl benzothiophene.
Detailed Description
Example 1
4-Bromobenzothiophene (40.00 g,187.71 mmol), anhydrous piperazine (80.85 g,938.56 mmol), L-hydroxyproline (24.61 g,187.71 mmol), cuprous oxide (5.37 g,37.54 mmol), anhydrous potassium carbonate (25.94 g,187.71 mmol) were weighed into a 1000mL flask, N-methyl-pyrrolidone (400 mL) was added, nitrogen was replaced 3 times, the temperature was raised to 130℃for 10 hours, after the reaction was completed, 800mL of water was added to dilute the system, extracted twice with dichloromethane, 400mL of each time was extracted, the organic phase was combined and dried with anhydrous magnesium sulfate to remove water, the filtrate was collected by filtration, and the organic phase was concentrated to obtain a reddish brown liquid. Adding 80mL of methanol and 400mL of acetone into the liquid, slowly dropwise adding 100mL of mixed solution of concentrated acetone hydrochloride, wherein 20mL of concentrated hydrochloric acid and 80mL of acetone are used for salifying and separating out target products, carrying out suction filtration to obtain an off-white solid, and drying to obtain 45.6g of 4-piperazinyl benzothiophene hydrochloride, wherein the yield is 95.3%, the purity is 99.6%, and mass spectrum data are shown in figure 1.
Comparative example 1
4-bromobenzothiophene (40.00 g,187.71 mmol), anhydrous piperazine (80.85 g,938.56 mmol), L-hydroxyproline (24.61 g,187.71 mmol), cuprous oxide (5.37 g,37.54 mmol) and anhydrous potassium carbonate (25.94 g,187.71 mmol) were weighed into a 1000mL flask, dimethyl sulfoxide (400 mL) was added to replace nitrogen 3 times, the reaction was heated to 130 ℃ for 10 hours, after the reaction was completed, 800mL of water was added to dilute the system, the system was extracted twice with dichloromethane, each 400mL of extraction was performed, the organic phase was combined and dried with anhydrous magnesium sulfate to remove water, the filtrate was collected by filtration, and the organic phase was concentrated to obtain a reddish brown liquid. Adding 80mL of methanol and 400mL of acetone into the liquid, slowly dropwise adding 100mL of mixed solution of concentrated acetone hydrochloride, wherein 20mL of concentrated hydrochloric acid and 80mL of acetone are used for salifying and separating out target products, carrying out suction filtration to obtain an off-white solid, and drying to obtain 40.5g of 4-piperazinyl benzothiophene hydrochloride, wherein the yield is 85.1%, and the purity is 99.7%.
Comparative example 2
4-Bromobenzothiophene (10.00 g,46.93 mmol), anhydrous piperazine (20.21 g,234.64 mmol), L-proline (5.40 g,46.93 mmol), cuprous oxide (1.34 g,9.38 mmol), anhydrous potassium carbonate (6.48 g,46.93 mmol) were weighed into a 250mL flask, N-methyl-pyrrolidone (100 mL) was added, nitrogen was replaced 3 times, the temperature was raised to 130℃for 10 hours, after the reaction was completed, 200mL of water was added to dilute the system, extracted twice with dichloromethane, 100mL of each time was extracted, the organic phase was combined and dried with anhydrous magnesium sulfate to remove water, the filtrate was collected by filtration, and the organic phase was concentrated to obtain a reddish brown liquid. Adding 20mL of methanol and 100mL of acetone into the liquid, slowly dropwise adding 25mL of mixed solution of concentrated acetone hydrochloride, wherein 5mL of concentrated hydrochloric acid and 20mL of acetone are added, the target product is salified and separated out, the off-white solid is obtained through suction filtration, 8.9g of 4-piperazinyl benzothiophene hydrochloride is obtained through drying, the yield is 74.7%, and the purity is 99.5%.
Comparative example 3
4-Bromobenzothiophene (10.00 g,46.91 mmol), anhydrous piperazine (12.12 g,140.82 mmol), L-hydroxyproline (6.15 g,46.91 mmol), cuprous iodide (0.89 g,4.7 mmol), potassium carbonate (6.48 g,46.91 mmol) were weighed into a 250mL flask, N-dimethylformamide (100 mL) was added, nitrogen was replaced 3 times, the temperature was raised to 110℃for 12 hours, after the reaction was completed, 200mL of water was added to dilute the system, extracted twice with dichloromethane, 100mL of each time was extracted, the organic phase was combined and dried with anhydrous magnesium sulfate to remove water, the filtrate was collected by filtration, and the organic phase was concentrated to obtain a reddish brown liquid. Adding 20mL of methanol and 100mL of acetone into the liquid, slowly dropwise adding 25mL of mixed solution of concentrated acetone hydrochloride, wherein 5mL of concentrated hydrochloric acid and 20mL of acetone are added, the target product is salified and separated out, the off-white solid is obtained through suction filtration, 4.6g of 4-piperazinyl benzothiophene hydrochloride is obtained through drying, the yield is 38.6%, and the purity is 99.3%.
Comparative example 4
4-Bromobenzothiophene (10.00 g,46.91 mmol), anhydrous piperazine (12.12 g,140.82 mmol), L-proline (5.40 g,46.91 mmol), cuprous iodide (0.89 g,4.7 mmol) and potassium carbonate (6.48 g,46.91 mmol) were weighed into a 250mL flask, N-dimethylformamide (100 mL) was added, nitrogen was replaced 3 times, the temperature was raised to 110℃for 12 hours, after the reaction was completed, 200mL of water was added to the system for dilution, extraction with dichloromethane was twice, 100mL of each extraction was performed, the organic phase was combined and dried with anhydrous magnesium sulfate for water removal, the filtrate was collected by filtration, and the organic phase was concentrated to obtain a reddish brown liquid. Adding 10mL of methanol and 100mL of acetone into the liquid, slowly dropwise adding 25mL of mixed solution of concentrated acetone hydrochloride, wherein 5mL of concentrated hydrochloric acid and 20mL of acetone are added, salifying and separating out target products, suction filtering to obtain off-white solid, and drying to obtain 2.3g of 4-piperazinyl benzothiophene hydrochloride, wherein the yield is 22.5%, and the purity is 99.3%.
Comparative examples 5 to 7
The differences between comparative examples 5 to 7 and example 1 are shown in Table 1, and the reaction conditions and the yield purity of each of comparative examples 1 to 7 as shown in Table 1 are summarized in the same manner as in example 1.
TABLE 1 reaction conditions and yields and purities of example 1, comparative examples 1-7
As can be seen from the data in Table 1, the present application, by selecting N-methyl-pyrrolidone as the solvent, can effectively increase the yield of the product as compared with N, N-dimethylformamide, and the present application can effectively increase the yield of the product by reducing the amount of the base, i.e., potassium carbonate, to a molar number equivalent to that of the raw material 4-bromobenzothiophene.
Those of ordinary skill in the art will appreciate that: the discussion of any of the embodiments above is merely exemplary and is not intended to suggest that the scope of protection of the application is limited to these examples; the technical features of the above embodiments or in the different embodiments may also be combined within the idea of the application, the steps may be implemented in any order and there are many other variations of the different aspects of one or more embodiments of the application as described above, which are not provided in detail for the sake of brevity.
One or more embodiments of the present application are intended to embrace all such alternatives, modifications and variations as fall within the broad scope of the present application. Accordingly, any omissions, modifications, equivalents, improvements and others which are within the spirit and principles of the one or more embodiments of the application are intended to be included within the scope of the application.
Claims (2)
1. A synthetic method of an epinastine intermediate is characterized in that 4-bromobenzothiophene, piperazine, L-hydroxyproline, cuprous oxide, potassium carbonate and N-methyl-pyrrolidone are mixed, and heated and reacted under a protective atmosphere to obtain 4-piperazinyl benzothiophene;
the molar ratio of the 4-bromobenzothiophene, the piperazine, the cuprous oxide, the L-hydroxyproline and the potassium carbonate is 1:5:0.2:1:1;
the weight-volume ratio of the total weight of the 4-bromobenzothiophene, the piperazine, the L-hydroxyproline, the cuprous oxide and the potassium carbonate to the N-methyl-pyrrolidone is 170-180 mg:400mL;
the reaction temperature of the heating reaction was 130 ℃.
2. A process for the synthesis of an intermediate of epipiprazole according to claim 1, characterized in that 4-piperazinyl benzothiophene is diluted with water, extracted with dichloromethane, the organic phases are combined and concentrated; adding methanol and acetone into the concentrated organic phase, then adding a mixed solution of concentrated acetone hydrochloride, and carrying out suction filtration to obtain the 4-piperazinyl benzothiophene hydrochloride.
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| CN104829602A (en) * | 2015-04-15 | 2015-08-12 | 重庆医药工业研究院有限责任公司 | Brexpiprazole preparation method |
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| CN109970705A (en) * | 2019-05-14 | 2019-07-05 | 浙江工业大学 | A method of it is standby according to piperazine azoles intermediate and according to a piperazine azoles using cheap metal copper |
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| US20170320862A1 (en) * | 2016-05-03 | 2017-11-09 | Cadila Healthcare Limited | Process for the preparation of brexpiprazole and intermediates thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104829602A (en) * | 2015-04-15 | 2015-08-12 | 重庆医药工业研究院有限责任公司 | Brexpiprazole preparation method |
| CN109422722A (en) * | 2017-08-29 | 2019-03-05 | 上海现代制药股份有限公司 | A kind of preparation method of benzothienyl compounds intermediate |
| CN109970705A (en) * | 2019-05-14 | 2019-07-05 | 浙江工业大学 | A method of it is standby according to piperazine azoles intermediate and according to a piperazine azoles using cheap metal copper |
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