CN111303043A - Preparation method of flibanserin hydrochloride - Google Patents
Preparation method of flibanserin hydrochloride Download PDFInfo
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- CN111303043A CN111303043A CN201910319671.7A CN201910319671A CN111303043A CN 111303043 A CN111303043 A CN 111303043A CN 201910319671 A CN201910319671 A CN 201910319671A CN 111303043 A CN111303043 A CN 111303043A
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- XGAGFLQFMFCIHZ-UHFFFAOYSA-N 3-[2-[4-[3-(trifluoromethyl)phenyl]piperazin-1-yl]ethyl]-1h-benzimidazol-2-one;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 XGAGFLQFMFCIHZ-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 39
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 19
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 19
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- GQFMHXZXWWIIAY-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]pyrazine Chemical compound FC(F)(F)C1=CC=CC(C=2N=CC=NC=2)=C1 GQFMHXZXWWIIAY-UHFFFAOYSA-N 0.000 claims abstract description 10
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 238000001035 drying Methods 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 20
- 239000007787 solid Substances 0.000 claims description 20
- 239000000243 solution Substances 0.000 claims description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000005311 nuclear magnetism Effects 0.000 claims description 16
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000012074 organic phase Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 9
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 239000008096 xylene Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000005457 ice water Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000002027 dichloromethane extract Substances 0.000 claims description 4
- 238000007599 discharging Methods 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000000967 suction filtration Methods 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 15
- 239000000543 intermediate Substances 0.000 abstract description 8
- -1 3-trifluoromethylphenyl pyrazine compound Chemical class 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 4
- 239000012467 final product Substances 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 description 5
- 229960002053 flibanserin Drugs 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000035946 sexual desire Effects 0.000 description 3
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 238000012795 verification Methods 0.000 description 2
- DGNLGWJZZZOYPT-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]piperazin-1-ium;chloride Chemical compound [Cl-].FC(F)(F)C1=CC=CC(N2CC[NH2+]CC2)=C1 DGNLGWJZZZOYPT-UHFFFAOYSA-N 0.000 description 1
- YFYVJMADMDQPCS-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]piperazine Chemical compound FC(F)(F)C1=CC=CC(C2NCCNC2)=C1 YFYVJMADMDQPCS-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002868 serotonin 5-HT1 receptor antagonist Substances 0.000 description 1
- 239000003215 serotonin 5-HT2 receptor antagonist Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of flibanserin hydrochloride. O-phenylenediamine and 3-trifluoromethylphenyl pyrazine are used as raw materials, wherein the o-phenylenediamine is reacted with ethyl acetoacetate to obtain a compound 10-1-G, a 3-trifluoromethylphenyl pyrazine compound I is subjected to two-step substitution reaction to obtain a compound 10-1-B, and the compound 10-1-B and the compound 10-1-G are subjected to substitution reaction to obtain a final product, namely flibanserin hydrochloride; aims at reducing cost, optimizing process and facilitating industrial production; the method has the advantages of simple and convenient operation, reasonable reaction flow, low production cost, good product quality, no pollution to the environment and suitability for industrial production, and the content is more than 99.5 percent.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, and particularly relates to a preparation method of flibanserin hydrochloride.
Background
Flibanserin (flibanserin), a drug used for increasing female sexual desire, reduces the 5-hydroxytryptamine inhibiting sexual desire to increase the level of dopamine stimulating sexual desire. Burlinger Inveheim, Germany, published results of a three-phase clinical trial of flibanserin at the European conference of sexuality on day 11, 16, 2009, which was said to show good efficacy and tolerability in pre-menopausal women with low libido (HSDD). The most key intermediate flibanserin hydrochloride has great potential in market prospect and economic benefit.
The synthesis route of flibanserin is reported in literature reported by literature [ TURCONI M, BIETTI G, GIRALDO E, et al, Benzimidazo-lonederivatives as 5-HT1A and 5-HT2 antagonists:1993003016[ P ]. 1993-02-18 ], wherein 1- (1-phenylalkenyl) -1, 3-dihydrobenzimidazolone is used as a raw material, and an intermediate 2, 2 and 1- (3-trifluoromethylphenyl) piperazine hydrochloride are condensed to obtain the intermediate flibanserin hydrochloride through alkylation and deprotection reactions. The raw material 1- (1-phenylalkenyl) -1, 3-dihydrobenzimidazolone is a commodity which is difficult to obtain in the market and expensive, and has certain limitation on the industrial production of flibanserin hydrochloride.
Currently, there is no commercially available and low-cost method for the preparation of flibanserin hydrochloride in the prior art.
Disclosure of Invention
The invention aims to provide a preparation method of flibanserin hydrochloride, which is suitable for industry and has low cost, aiming at the defects and shortcomings of the prior art; in particular to a method for synthesizing a key intermediate flibanserin hydrochloride of flibanserin.
In order to achieve the purpose, the invention adopts the technical scheme that: the flibanserin hydrochloride is specifically as follows:
the preparation method of the flibanserin hydrochloride comprises the following steps:
1. using dimethylbenzene as a solvent and KOH as an accelerator, carrying out condensation reaction on o-phenylenediamine and ethyl acetoacetate serving as raw materials at the temperature of 100-140 ℃, then crystallizing at low temperature, and drying to obtain a compound 10-1-G;
2. dissolving hydrochloride of 3-trifluoromethyl phenyl pyrazine in a mixed solvent of NaOH aqueous solution and acetone, performing substitution reaction with bromoethanol at 50-70 ℃, and extracting and drying to obtain a compound 10-1-E;
3. dissolving the compound 10-1-E in dichloroethane, dropwise adding thionyl chloride, and carrying out nucleophilic substitution reaction at 70-90 ℃; cooling with ice water, adjusting pH value, extracting, and drying to obtain compound 10-1-B;
4. performing nucleophilic substitution reaction on the compound 10-1-B and the compound 10-1-G at the temperature of 60-80 ℃ by using dimethyl sulfoxide as a solvent and concentrated potassium carbonate as an accelerator, and extracting and drying to obtain flibanserin hydrochloride;
preferably, the molar ratio of the o-phenylenediamine to the ethyl acetoacetate in the step 1 is 1: 0.9-1.2; the temperature of the substitution reaction is 105-150 ℃.
Preferably, the compound 3-trifluoromethylphenylpyrazine hydrochloride, bromoethanol and NaOH in the step 2 are used in a molar ratio of 1: 1-1.5: 1.5-4; the reaction temperature is 40-60 ℃.
Preferably, the compound 10-1-E and thionyl chloride in the step 3 are used in a molar ratio of 1: 2-4; the temperature is controlled at 60-80 ℃.
Preferably, the compound 10-1-B and the compounds 10-1-G and K in the step 42CO3The molar ratio of the used amount is 1: 0.9-1.1: 2-3; the temperature is controlled at 50-70 ℃, and dimethyl sulfoxide is used as a solvent in the reaction.
The technical conception of the invention is as follows: the method comprises the steps of replacing 1- (1-phenylalkenyl) -1, 3-dihydrobenzimidazolone which is reported in literature with commercially available and cheap o-phenylenediamine as a starting material, carrying out condensation reaction to obtain an intermediate 10-1-G, carrying out two-step substitution reaction on the intermediate 10-1-B and 3-trifluoromethylphenyl pyrazine to obtain a final product, namely flibanserin hydrochloride.
Compared with the prior art, the technical scheme of the invention has the advantages and beneficial effects that:
firstly, the method replaces the 1- (1-phenylalkenyl) -1, 3-dihydrobenzimidazolone which is reported in the literature with the commercially available o-phenylenediamine, so that the industrial implementation is easier.
Secondly, because the price of the o-phenylenediamine is low, the production cost of the final product is about 50 percent of the original cost.
And thirdly, the product has good quality, the content is more than 99.5 percent, no pollution is caused to the environment, and the method is suitable for industrial production.
Detailed Description
The flibanserin hydrochloride in the specific embodiment is specifically as follows:
the first embodiment is as follows:
a preparation method of flibanserin hydrochloride comprises the following steps:
1. synthesis of Compound 10-1-G
3kg of o-phenylenediamine, 4.5kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene are put into a 50L oil bath heating kettle, the heating is carried out to 120 ℃, reflux reaction is carried out for 2 hours, cooling crystallization, suction filtration and rinsing with a small amount of xylene are carried out, so as to obtain 10-1-G with the wet weight of gray solid, and the yield of the product is 81 percent through nuclear magnetism verification.
2. Synthesis of Compound 10-1-E
Dissolving 5Kg of hydrochloride of 3-trifluoromethylphenylpyrazine in 2.873Kg of NaOH12.5L aqueous solution, adding 12.5L of acetone into a 50L reaction kettle, stirring at room temperature, adding 3.843Kg of 2-bromoethanol, reacting at 60 ℃ for 4 hours, after the reaction is finished, spin-drying the acetone, adding 20L of water, extracting for 3 times by using dichloromethane, combining dichloromethane extract liquor, washing for 2 times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 5Kg of light yellow liquid 10-1-E. The product is verified by nuclear magnetism, and the yield is 95%.
3. Synthesis of Compound 10-1-B
2.5kg of 10-1-E were dissolved in 25L of dichloroethane, and SOCl was added dropwise at room temperature23.931Kg, and the mixture is heated to 80 ℃ after dropping to react for 4 hours. The reaction solution was poured into 25L of ice water, the pH was adjusted to about 10 with NaOH solution, extracted 2 times with dichloromethane, the organic phases were combined, dried, filtered once with silica gel and spin-dried to give 2.35kg10-1-B as a dark oil. The product is verified by nuclear magnetism, and the yield is 88%.
4. Synthesis of the Compound flibanserin hydrochloride
10-1-G 2.385KG、10-1-B 4.534KG、K2CO3Adding 5.27KG and 18L dimethyl sulfoxide into a 50L oil bath kettle, reacting for 8 hours at 70 ℃, and after TLC, pouring the reaction liquid into water, and adding dichloromethaneExtraction was performed 3 times, organic phases were combined, washed with water 2 times, washed with saturated brine once, dried over anhydrous sodium sulfate, and spin-dried to obtain a gray solid.
Dissolving gray solid in 25L of ethanol under heating, adding 6L of concentrated HCl, reacting at 70 deg.C for 2 hr, discharging reaction solution, adding 15L of ethanol, cooling to room temperature, separating out solid, vacuum filtering, and rinsing with ethanol to obtain white solid 4.4 kg. The product is verified by nuclear magnetism, and the yield is 76%.
Example two:
a preparation method of flibanserin hydrochloride comprises the following steps:
1. synthesis of Compound 10-1-G
3kg of o-phenylenediamine, 4.1kg of ethyl acetoacetate, 100ml of KOH solution and 19L of xylene are put into a 50L oil bath heating kettle, the heating is carried out to 140 ℃, reflux reaction is carried out for 2 hours, cooling crystallization, suction filtration and rinsing with a small amount of xylene are carried out, so as to obtain 10-1-G with the wet weight of gray solid, and the yield is 80 percent by nuclear magnetism of the product.
2. Synthesis of Compound 10-1-E
Dissolving 5Kg of hydrochloride of 3-trifluoromethylphenylpyrazine in 2.973Kg of NaOH12.5L aqueous solution, adding 12.5L of acetone into a 50L reaction kettle, stirring at room temperature, adding 3.943Kg of 2-bromoethanol, reacting at 70 ℃ for 4 hours, after the reaction is finished, spin-drying the acetone, adding 20L of water, extracting for 4 times by using dichloromethane, combining dichloromethane extract liquor, washing for 2 times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 5Kg of light yellow liquid 10-1-E. The product is verified by nuclear magnetism, and the yield is 94%.
3. Synthesis of Compound 10-1-B
2.5kg of 10-1-E were dissolved in 25L of dichloroethane, and SOCl was added dropwise at room temperature24.00Kg, and the mixture is heated to 70 ℃ after dropping and reacted for 4 hours. The reaction solution was poured into 25L of ice water, the pH was adjusted to about 10 with NaOH solution, extracted 3 times with dichloromethane, the organic phases were combined, dried, filtered once with silica gel and spin-dried to give 2.45kg10-1-B as a dark oil. The product is verified by nuclear magnetism, and the yield is 8805%.
4. Synthesis of the Compound flibanserin hydrochloride
10-1-G 2.485KG、10-1-B 4.634KG、K2CO35.37KG and 18L dimethyl sulfoxide are added into a 50L oil bath kettle and reacted for 8 hours at 65 ℃, TLC shows that the raw materials are reacted completely, the reaction solution is poured into water, dichloromethane is used for extraction for 3 times, organic phases are combined, water is used for washing for 2 times, saturated saline solution is used for washing once, anhydrous sodium sulfate is dried, and the gray solid is obtained after spin drying.
Dissolving gray solid in 25L of ethanol under heating, adding 6L of concentrated HCl, reacting at 68 ℃ for 2 hours, discharging reaction liquid after the reaction is finished, adding 15L of ethanol, cooling to room temperature, separating out solid, filtering, and rinsing with ethanol to obtain 4.4kg of white solid. The product is verified by nuclear magnetism, and the yield is 75.5%.
Example three:
a preparation method of flibanserin hydrochloride comprises the following steps:
1. synthesis of Compound 10-1-G
3kg of o-phenylenediamine, 3.8kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene are put into a 50L oil bath heating kettle, the heating is carried out to 140 ℃, reflux reaction is carried out for 2 hours, cooling crystallization, suction filtration and rinsing with a small amount of xylene are carried out, so as to obtain 10-1-G with the wet weight of gray solid, and the yield of the product is 83 percent through nuclear magnetism verification.
2. Synthesis of Compound 10-1-E
Dissolving 5Kg of hydrochloride of 3-trifluoromethylphenylpyrazine in 2.773Kg of NaOH12.5L aqueous solution, adding 12.5L of acetone into a 50L reaction kettle, stirring at room temperature, adding 3.743Kg of 2-bromoethanol, reacting at 50 ℃ for 4 hours, after the reaction is finished, spin-drying the acetone, adding 20L of water, extracting for 3 times by using dichloromethane, combining dichloromethane extract liquor, washing for 2 times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 5Kg of light yellow liquid 10-1-E. The product is verified by nuclear magnetism, and the yield is 94%.
3. Synthesis of Compound 10-1-B
2.5kg of 10-1-E were dissolved in 25L of dichloroethane, and SOCl was added dropwise at room temperature23.831Kg, and the mixture is heated to 75 ℃ after dropping to react for 4 hours. Pouring the reaction solution into 25L ice water, adjusting pH to about 10 with NaOH solution, extracting with dichloromethane for 2 times, mixing organic phases, drying, filtering with silica gel once, and spin-drying to obtain dark oily liquid2.35kg of 10-1-B. The product is verified by nuclear magnetism, and the yield is 87.5%.
4. Synthesis of the Compound flibanserin hydrochloride
10-1-G 2.285KG、10-1-B 4.434KG、K2CO35.17KG and 18L dimethyl sulfoxide are added into a 50L oil bath kettle and reacted for 8 hours at the temperature of 58 ℃, TLC shows that the raw materials are reacted completely, the reaction solution is poured into water, dichloromethane is used for extraction for 3 times, organic phases are combined, water is used for 3 times, saturated saline solution is used for washing once, anhydrous sodium sulfate is dried, and the gray solid is obtained after spin drying.
Dissolving gray solid in 25L of ethanol under heating, adding 6L of concentrated HCl, reacting at 65 ℃ for 2 hours, discharging reaction liquid after the reaction is finished, adding 15L of ethanol, cooling to room temperature, separating out solid, filtering, and rinsing with ethanol to obtain 4.4kg of white solid. The product was confirmed by nuclear magnetism to have a yield of 77%.
The invention aims to reduce the cost, optimize the process and facilitate the industrial production. The principle is that o-phenylenediamine and 3-trifluoromethylphenyl pyrazine are used as raw materials, wherein the o-phenylenediamine is reacted with ethyl acetoacetate to obtain a compound 10-1-G, a 3-trifluoromethylphenyl pyrazine compound I is subjected to two-step substitution reaction to obtain a compound 10-1-B, and the compound 10-1-B and the compound 10-1-G are subjected to substitution reaction to obtain a final product, namely flibanserin hydrochloride. The method has the advantages of simple and convenient operation, reasonable reaction flow, low production cost, good product quality, no pollution to the environment and suitability for industrial production, and the content is more than 99.5 percent.
The above description is only for the purpose of illustrating the technical solutions of the present invention and not for the purpose of limiting the same, and other modifications or equivalent substitutions made by those skilled in the art to the technical solutions of the present invention should be covered within the scope of the claims of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (6)
1. A preparation method of flibanserin hydrochloride is characterized by comprising the following steps: the flibanserin hydrochloride is:
the preparation method comprises the following steps:
(1) the method comprises the following steps of taking dimethylbenzene as a solvent and KOH as an accelerator, carrying out condensation reaction on o-phenylenediamine and ethyl acetoacetate serving as raw materials at the temperature of 100-140 ℃, then crystallizing at low temperature, and drying to obtain a compound 10-1-G;
(2) dissolving hydrochloride of the 3-trifluoromethyl phenyl pyrazine in a mixed solvent of NaOH aqueous solution and acetone, performing substitution reaction with bromoethanol at 50-70 ℃, and extracting and drying to obtain a compound 10-1-E;
(3) dissolving the compound 10-1-E in dichloroethane, dropwise adding thionyl chloride, and carrying out nucleophilic substitution reaction at 70-90 ℃; cooling with ice water, adjusting pH value, extracting, and drying to obtain compound 10-1-B;
(4) and performing nucleophilic substitution reaction on the compound 10-1-B and the compound 10-1-G at the temperature of 60-80 ℃ by using dimethyl sulfoxide as a solvent and concentrated potassium carbonate as an accelerator, and extracting and drying to obtain flibanserin hydrochloride.
2. The process according to claim 1, characterized in that: in the step 1, the molar ratio of the usage amount of o-phenylenediamine to the usage amount of ethyl acetoacetate is 1: 0.9-1.2; the temperature of the substitution reaction is 105-150 ℃.
3. The process according to claim 1, characterized in that: the use molar ratio of hydrochloride of the compound 3-trifluoromethyl phenyl pyrazine in the step 2 to the use amount of bromoethanol to NaOH is 1: 1-1.5: 1.5-4; the reaction temperature is 40-60 ℃.
4. The process according to claim 1, characterized in that: the molar ratio of the compound 10-1-E to the thionyl chloride in the step 3 is 1: 2-4; the temperature is controlled at 60-80 ℃.
5. The process according to claim 1, characterized in that: the compound in the step 410-1-B and Compounds 10-1-G and K2CO3The molar ratio of the used amount is 1: 0.9-1.1: 2-3; the temperature is controlled at 50-70 ℃, and dimethyl sulfoxide is used as a solvent in the reaction.
6. The process according to claim 1, characterized in that: the preparation method comprises the following steps:
(1) synthesis of Compound 10-1-G
Putting 3kg of o-phenylenediamine, 4.5kg of ethyl acetoacetate, 100ml of KOH solution and 18L of xylene into a 50L oil bath heating kettle, heating to 120 ℃, carrying out reflux reaction for 2 hours, cooling, crystallizing, carrying out suction filtration, rinsing with a small amount of xylene to obtain 4.2kg of 10-1-G of gray solid wet weight, and confirming the yield of 81% of a product by nuclear magnetism;
(2) synthesis of Compound 10-1-E
Dissolving 5Kg of hydrochloride of 3-trifluoromethylphenylpyrazine in 2.873Kg of NaOH12.5L aqueous solution, adding 12.5L of acetone into a 50L reaction kettle, stirring at room temperature, adding 3.843Kg of 2-bromoethanol, reacting for 4 hours at 60 ℃, after the reaction is finished, spin-drying the acetone, adding 20L of water, extracting for 3 times by using dichloromethane, combining dichloromethane extract liquor, washing for 2 times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and spin-drying to obtain 5Kg of light yellow liquid 10-1-E; the product is verified by nuclear magnetism, and the yield is 95%;
(3) synthesis of Compound 10-1-B
2.5kg of 10-1-E were dissolved in 25L of dichloroethane, and SOCl was added dropwise at room temperature23.931Kg, and the mixture is heated to 80 ℃ after dropping to react for 4 hours. The reaction solution was poured into 25L of ice water, the pH was adjusted to about 10 with NaOH solution, extracted 2 times with dichloromethane, the organic phases were combined, dried, filtered once with silica gel and spin-dried to give 2.35kg10-1-B as a dark oil. The product is verified by nuclear magnetism, and the yield is 88%;
(4) and synthesis of flibanserin hydrochloride
10-1-G2.385KG、10-1-B4.534KG、K2CO3Adding 5.27KG and 18L dimethyl sulfoxide into 50L oil bath kettle, reacting at 70 deg.C for 8 hr, TLC showing that the raw materials are reacted completely, pouring the reaction solution into water, extracting with dichloromethane for 3 times, and mixingWashing the organic phase with water for 2 times, washing the organic phase with saturated saline solution for one time, drying the organic phase with anhydrous sodium sulfate, and spin-drying the organic phase to obtain a gray solid;
dissolving gray solid in 25L of ethanol under heating, adding 6L of concentrated HCl, reacting at 70 deg.C for 2 hr, discharging reaction solution, adding 15L of ethanol, cooling to room temperature, separating out solid, vacuum filtering, and rinsing with ethanol to obtain white solid 4.4 kg; the product is verified by nuclear magnetism, and the yield is 76%.
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| CN1551879A (en) * | 2001-08-02 | 2004-12-01 | ���������ﻯѧ����˾ | Stable polymorph of FLIBANSERIN, technical process for its preparation and the use thereof for preparing medicaments |
| CN106749038A (en) * | 2015-11-25 | 2017-05-31 | 山东诚创医药技术开发有限公司 | A kind of preparation method of flibanserin |
| CN108456173A (en) * | 2018-02-05 | 2018-08-28 | 南京法恩化学有限公司 | A kind of preparation method of flibanserin |
| CN109384680A (en) * | 2017-08-09 | 2019-02-26 | 广州朗圣药业有限公司 | A kind of preparation method of flibanserin intermediate |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1551879A (en) * | 2001-08-02 | 2004-12-01 | ���������ﻯѧ����˾ | Stable polymorph of FLIBANSERIN, technical process for its preparation and the use thereof for preparing medicaments |
| CN106749038A (en) * | 2015-11-25 | 2017-05-31 | 山东诚创医药技术开发有限公司 | A kind of preparation method of flibanserin |
| CN109384680A (en) * | 2017-08-09 | 2019-02-26 | 广州朗圣药业有限公司 | A kind of preparation method of flibanserin intermediate |
| CN108456173A (en) * | 2018-02-05 | 2018-08-28 | 南京法恩化学有限公司 | A kind of preparation method of flibanserin |
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Address after: 437200, Hubei Province, Jiayu County, Xianning Province Pan Wan fan Lake Industrial Park Applicant after: Hubei Wanzhi Chemical Pharmaceutical Co.,Ltd. Applicant after: WUHAN TECHNOLOGY AND BUSINESS University Address before: 437200, Hubei Province, Jiayu County, Xianning Province Pan Wan fan Lake Industrial Park Applicant before: WUHAN WANZHI CHEMICAL MEDICINE Co.,Ltd. Applicant before: WUHAN TECHNOLOGY AND BUSINESS University |
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Application publication date: 20200619 |