CN116947691B - Preparation method of fluvoxamine maleate - Google Patents
Preparation method of fluvoxamine maleate Download PDFInfo
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- CN116947691B CN116947691B CN202310996588.XA CN202310996588A CN116947691B CN 116947691 B CN116947691 B CN 116947691B CN 202310996588 A CN202310996588 A CN 202310996588A CN 116947691 B CN116947691 B CN 116947691B
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- LFMYNZPAVPMEGP-PIDGMYBPSA-N Fluvoxamine maleate Chemical compound OC(=O)\C=C/C(O)=O.COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 LFMYNZPAVPMEGP-PIDGMYBPSA-N 0.000 title claims abstract description 77
- 229960002107 fluvoxamine maleate Drugs 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 28
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 17
- 229960004038 fluvoxamine Drugs 0.000 claims abstract description 14
- -1 fluvoxamine oxime Chemical class 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 4
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 66
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 36
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 22
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 22
- 239000011976 maleic acid Substances 0.000 claims description 22
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 12
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000002425 crystallisation Methods 0.000 claims description 5
- 230000008025 crystallization Effects 0.000 claims description 5
- 239000012458 free base Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 claims description 4
- UDCRPPVSQRFBKJ-UHFFFAOYSA-N n-[5-methoxy-1-[4-(trifluoromethyl)phenyl]pentylidene]hydroxylamine Chemical compound COCCCCC(=NO)C1=CC=C(C(F)(F)F)C=C1 UDCRPPVSQRFBKJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 22
- 230000000694 effects Effects 0.000 abstract description 18
- 239000003513 alkali Substances 0.000 abstract description 11
- 239000000047 product Substances 0.000 abstract description 11
- 238000007670 refining Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 239000002699 waste material Substances 0.000 abstract description 6
- 239000003960 organic solvent Substances 0.000 abstract description 4
- 239000007864 aqueous solution Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 24
- 238000001514 detection method Methods 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000001914 filtration Methods 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 239000005457 ice water Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical group C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 231100000024 genotoxic Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FSOHAZRWBCMLRR-ODZAUARKSA-N [F].OC(=O)\C=C/C(O)=O Chemical compound [F].OC(=O)\C=C/C(O)=O FSOHAZRWBCMLRR-ODZAUARKSA-N 0.000 description 1
- 125000005219 aminonitrile group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- YGSFNCRAZOCNDJ-UHFFFAOYSA-N propan-2-one Chemical compound CC(C)=O.CC(C)=O YGSFNCRAZOCNDJ-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/14—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/12—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reactions not involving the formation of oxyimino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of drug synthesis processes, and particularly relates to a preparation method of fluvoxamine maleate with high purity and high yield. The invention takes fluvoxamine oxime and 2-chloroethylamine hydrochloride as raw materials, takes n-butanol as solvent, and carries out substitution reaction in the presence of alkali to prepare a crude fluvoxamine maleate product; recrystallizing the crude product of fluvoxamine maleate by an alkaline aqueous solution to obtain the high-purity fluvoxamine maleate. The invention adopts a one-pot process, has short reaction period and high production efficiency, and has good removal effect on impurities such as impurity F without using any organic solvent when refining crude products, and the obtained fluvoxamine maleate has high purity, high process yield and less three wastes output.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of fluvoxamine maleate with high purity and high yield.
Background
Fluvoxamine maleate, 2- [ [ [ (1E) -5-methoxy-1- [4- (trifluoromethyl) phenyl ] pentylidene ] amino ] oxy ] ethanamine maleate, english name Fluvoxamine Maleate. Fluvoxamine maleate is 5-hydroxytryptamine reuptake inhibitor (SSRI), which is an antidepressant widely applied in clinic at present, and has the action mechanism of selectively inhibiting reuptake of 5-HT by a central nervous presynaptic membrane, increasing 5-HT concentration at a synaptic cleft and achieving the purpose of antidepressant. Fluvoxamine maleate is marketed in europe in 1994, japan in 1999 and the united states in 2001. At present, only common tablet of fluvoxamine maleate is sold in China domestic market, such as 'Lanyan' imported from yapei and 'Rui Bile' produced by Lizhu pharmacy.
The structural formula of fluvoxamine maleate is as follows:
U.S. patent documents US4085225 and US4086361 disclose that 5-methoxy-4-trifluorobenzyl pentanone is used as a starting material, and is subjected to oximation reaction with hydroxylamine hydrochloride to prepare fluvoxamine oxime, and then the fluvoxamine oxime is reacted with propylene oxide, wherein the reacted product is subjected to column chromatography and then used for the next step, and after hydroxy is activated by methanesulfonic acid, the reaction product is reacted with ammonia gas to prepare fluvoxamine. The propylene oxide and the ammonia gas used in the route are gases at normal temperature, which are unfavorable for industrialized production control, the propylene oxide is a genotoxic impurity, and the methylsulfonic acid is easy to produce sulfonate genotoxic impurity with reaction materials, which is unfavorable for quality control of products. The intermediates in each step of the route need to be separated and purified, and particularly the oximated aminonitrile product needs to be purified by column chromatography, so that the method is not suitable for large-scale and commercial production.
U.S. patent documents US4085225 and US4086361 also disclose a preparation method using fluvoxamine oxime and 2-chloroethylamine hydrochloride as starting materials, DMF as reaction solvent and potassium hydroxide as acid binding agent. After 2 days of reaction, the fluvoxamine maleate is prepared by the procedures of acid regulation, ether washing, alkali regulation, ether extraction, alkali liquor washing, anhydrous sodium sulfate drying and the like, filtering, concentrating the obtained solvent to dryness, dissolving in ethanol, adding maleic acid, evaporating the solvent to dryness, and recrystallizing with acetonitrile. The preparation of the fluvoxamine in the route needs 2 days, the reaction time is long, the reaction is carried out step by step, each step needs post-treatment, three wastes are generated, the post-treatment needs continuous acid adjustment, alkali adjustment, multiple solvent extraction and washing, the operation is complex, and the three wastes discharge amount is large. Because of the high content of impurity F, the crude product is refined by using an organic solvent and needs to be refined for multiple times, the product yield is low, and the cost is high.
Under the prior art, although the preparation methods of fluvoxamine maleate are various, the problems of long production period, large three-waste output, high impurity content of key processes such as impurity F and the like exist. The impurity F has the following structural formula:
the existing route has poor effect of removing the impurity F in the preparation and refining processes of the fluvoxamine maleate, and the problem is always a key technical problem for restricting the amplified production of the fluvoxamine maleate.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a method for synthesizing fluvoxamine maleate by a one-pot method, which has short production period and less three-waste output. The impurity F can be effectively removed without using any organic solvent when refining the crude product. The method has the advantages of low production cost, simple operation, high yield and mild reaction conditions, and is suitable for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
(1) N-hydroxy-5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentaneimine (fluvoxamine oxime) and 2-chloroethylamine hydrochloride react with N-butanol as a solvent in the presence of sodium hydroxide to prepare fluvoxamine free base through substitution reaction;
(2) Adding water into the reaction liquid in the step (1), separating the liquid, and adding maleic acid into an organic phase to form salt to prepare a crude product of fluvoxamine maleate;
(3) And (3) adding water into the crude product of fluvoxamine maleate obtained in the step (2), heating to dissolve, adjusting the pH to 5.0-6.0 by using sodium carbonate, and cooling and crystallizing to obtain fluvoxamine maleate.
The specific synthetic route is as follows:
the reaction temperature in the step (1) is 20-50 ℃, preferably 30-35 ℃.
The molar ratio of the fluvoxamine oxime to the 2-chloroethylamine hydrochloride to the sodium hydroxide in the step (1) is 1:1.0-1.3:2.0-5.0, preferably 1:1.05:3.5.
The feeding ratio of the fluorine maleate to the voxamine oxime in the step (2) is 0.9-1.4:1, preferably 1.0:1.
The salt formation temperature of the fluvoxamine and the maleic acid free base in the step (2) is 5-45 ℃, preferably 20-30 ℃.
The dissolution temperature of the crude product in the step (3) is 40-55 ℃, preferably 40-45 ℃. The crystallization temperature is 3 to 30 ℃, preferably 10 to 15 ℃.
The pH in the step (3) is 5.0 to 6.0, preferably 5.3 to 5.5.
By applying the technical scheme, compared with the prior art, the invention has the following advantages:
(1) The invention uses n-butanol as a reaction solvent, adopts a one-pot process to prepare the fluvoxamine maleate, has short reaction period and high production efficiency;
(2) The output of three wastes is effectively reduced, and the method is environment-friendly;
(3) The reaction condition is mild, and the operation is simple;
(4) The crude product can be purified without any organic solvent, has good effect of removing impurities such as impurity F, and the obtained product has high yield, high purity and low production cost, and is suitable for industrial production.
Drawings
FIG. 1 shows a nuclear magnetic resonance hydrogen spectrum (H-NMR) of fluvoxamine maleate prepared by the method of the invention
FIG. 2 is a Mass Spectrum (MS) of fluvoxamine maleate prepared by the method of the present invention.
FIG. 3 is a liquid phase diagram (HPLC) of fluvoxamine maleate prepared by the method of the present invention.
Detailed Description
The foregoing is further elaborated by the following description of embodiments of the present invention, which are not to be construed as limiting the invention, but rather are defined by the claims, wherein the following embodiments are accomplished by the use of conventional techniques, except as specifically indicated. Specific examples are set forth below:
example 1 influence of different reaction solvents on yield and quality of fluvoxamine maleate
(1) 80g of different reaction solvents are added into a 1000mL three-port bottle, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, 20.0g of fluvone Sha Mingwo is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is added into the reaction system in a dropwise manner. After the dripping, the mixture is reacted for 2 hours at the temperature of 30-35 ℃.
(2) After the reaction is completed, 40g of water is added, stirring is carried out for 10min, 8.5g of maleic acid is added into an organic phase, stirring is carried out for 2.5h at 20-30 ℃, and a crude product of fluvoxamine maleate is obtained by filtering.
(3) 160g of water is added into the fluvoxamine maleate crude product, the temperature is raised to 45 ℃, sodium carbonate is added to adjust the pH value to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtering is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of the different reaction solvents of step (1) on fluvoxamine maleate yield, purity and removal of impurity F is shown in table 1.
TABLE 1
| Sequence number | Reaction solvent | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | N-butanol | 89.2 | 99.98 | Not detected |
| 2 | 2-methyltetrahydrofuran | 33.2 | 99.92 | 0.02 |
| 3 | Toluene (toluene) | 28.3 | 99.82 | 0.08 |
| 4 | N-heptane | 5.7 | 99.69 | 0.02 |
| 5 | Absolute ethyl alcohol | — | — | — |
| 6 | Acetone (acetone) | — | — | — |
| 7 | Dimethyl sulfoxide | — | — | — |
| 8 | Dichloromethane (dichloromethane) | — | — | — |
Experimental results show that fluvoxamine maleate cannot be prepared by using absolute ethyl alcohol, acetone, dimethyl sulfoxide, dichloromethane and the like as solvents. The target product can be obtained by selecting n-butanol, 2-methyltetrahydrofuran, toluene and n-heptane, and the n-butanol is used with the best effect by combining factors such as yield, quality and the like.
EXAMPLE 2 step (1) Effect of different bases on yield and quality of fluvoxamine maleate
(1) To a 1000mL three-necked flask, 80g of n-butanol was added, stirring was started, different bases (3.5 equivalents) were added, heating was carried out to 30℃to 35℃and 20.0g of fluvov Sha Mingwo was added, and a mixed solution of 9.8g of 2-chloroethylamine hydrochloride and 20g of water was added dropwise to the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The influence of different temperatures in the step (1) on the yield and quality of fluvoxamine maleate is shown in table 2.
TABLE 2
| Sequence number | Alkali | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | Sodium hydroxide | 89.2 | 99.98 | Not detected |
| 2 | Potassium hydroxide | 66.1 | 97.15 | 0.12 |
| 3 | Sodium carbonate | 32.2 | 78.74 | 0.03 |
| 4 | Sodium bicarbonate | 10.6 | 56.81 | 0.04 |
| 5 | Triethylamine | — | — | — |
Experimental results show that triethylamine is selected as alkali and no target product is generated; the target product can be obtained by using sodium hydroxide, potassium hydroxide, sodium carbonate and sodium bicarbonate as alkali, and the sodium hydroxide has the best effect by combining factors such as yield, quality and the like.
EXAMPLE 3 Effect of sodium hydroxide amount in step (1) on yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, sodium hydroxide with different equivalent weights is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of different sodium hydroxide dosages in step (1) on the yield and quality of fluvoxamine maleate is shown in Table 3.
TABLE 3 Table 3
Experimental results show that the optimal condition of the sodium hydroxide feeding amount in the step (1) is 3.5 equivalents based on factors such as comprehensive yield, quality and the like.
Example 4 influence of the reaction temperature in step (1) on the yield and quality of fluvoxamine maleate
(1) To a 1000mL three-necked flask, 80g of n-butanol was added, stirring was started, 10.4g of sodium hydroxide was added, the flask was heated to a certain temperature, 20.0g of fluorous volts Sha Mingwo was added, and a mixed solution of 9.8g of 2-chloroethylamine hydrochloride and 20g of water was added dropwise to the reaction solution. The mixed solution is reacted for 2 hours under the same temperature condition.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of different reaction temperatures in step (1) on the yield and quality of fluvoxamine maleate is shown in Table 4.
TABLE 4 Table 4
| Sequence number | Temperature (. Degree. C.) | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | 30～35 | 89.2 | 99.98 | Not detected |
| 2 | 20～25 | 34.6 | 98.75 | Not detected |
| 3 | 45～50 | 62.3 | 97.52 | 0.35 |
Experimental results show that the optimal reaction temperature condition of the step (1) is 30-35 ℃ according to factors such as comprehensive yield, quality and the like.
Example 5 influence of the amount of 2-chloroethylamine hydrochloride in step (1) on the yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and the mixed solution of 20g of 2-chloroethylamine hydrochloride/water with different equivalent weights is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of the different amounts of 2-chloroethylamine hydrochloride in step (1) on the yield and quality of fluvoxamine maleate is shown in Table 5.
TABLE 5
Experimental results show that the optimal condition of the dosage of the 2-chloroethylamine hydrochloride in the step (1) is 1.05 equivalents by combining factors such as yield, quality and the like.
Example 6 influence of the amount of maleic acid used in step (2) on the yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction is completed, 40g of water is added, the mixture is stirred for 10min, the organic phase is separated, different equivalents of maleic acid are added, and the mixture is stirred for 2.5h at the temperature of 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of different maleic acid amounts in step (2) on the yield and quality of fluvoxamine maleate is shown in table 6.
TABLE 6
Experimental results show that the optimal condition of the feeding amount of the maleic acid in the step (2) is 1.0 equivalent by combining factors such as yield, quality and the like.
EXAMPLE 7 influence of the salt formation temperature of step (2) on the yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water was added, the mixture was stirred for 10 minutes, 8.5g of maleic acid was added to the organic phase, and the mixture was stirred for 2.5 hours at a given temperature.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of different salifying temperatures in step (2) on the yield and quality of fluvoxamine maleate is shown in Table 7.
TABLE 7
| Sequence number | Temperature (. Degree. C.) | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | 5～15 | 84.5 | 94.63 | 0.02 |
| 2 | 20～30 | 89.2 | 99.98 | Not detected |
| 3 | 35～45 | 80.5 | 98.93 | 0.05 |
| 4 | 55～65 | 58.2 | 96.95 | 0.10 |
Experimental results show that the optimal conditions of the salt forming temperature in the step (2) are 20-30 ℃ according to factors such as comprehensive yield, quality and the like. EXAMPLE 8 step (3) influence of refining dissolution temperature of crude fluvoxamine maleate on yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to a certain temperature, sodium carbonate is added to adjust the pH value to 5.3-5.5, the temperature is naturally reduced to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and ice water is used for washing the filter cake. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The influence of the refining and dissolving temperature of the crude product of fluvoxamine maleate in the step (3) on the yield and quality of fluvoxamine maleate is shown in table 8.
TABLE 8
| Sequence number | Temperature (. Degree. C.) | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | 40～45 | 89.2 | 99.98 | Not detected |
| 2 | 50～55 | 84.3 | 98.58 | Not detected |
| 3 | 60～65 | 81.0 | 97.65 | Not detected |
Experimental results show that the reaction system can not be dissolved and cleared at the temperature lower than 40 ℃. And (3) synthesizing factors such as yield, quality and the like, wherein the optimal temperature condition for refining and dissolving the fluvoxamine maleate crude product in the step (3) is 40-45 ℃.
Example 9 step (3) refining of crude fluvoxamine maleate the effect of different types of bases to adjust pH on yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH to 5.3-5.5, the temperature is naturally cooled to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: the detection method of substances related to Chinese pharmacopoeia.
The effect of different types of alkali adjustment pH on the yield and quality of fluvoxamine maleate refined by the fluvoxamine maleate crude product in the step (3) is shown in table 9.
TABLE 9
| Sequence number | Alkali | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | Sodium carbonate | 89.2 | 99.98 | Not detected |
| 2 | Potassium hydroxide | 75.3 | 98.71 | 0.05 |
| 3 | Sodium hydroxide | 64.2 | 96.58 | 0.07 |
| 4 | Ammonia water | 34.2 | 92.05 | 0.21 |
Experimental results show that different types of alkali such as sodium carbonate, potassium hydroxide, sodium hydroxide, ammonia water and the like are used for adjusting the pH, the alkali has certain removing capacity for the impurity F, factors such as comprehensive yield, quality and the like, and the effect is optimal when sodium carbonate is used.
EXAMPLE 10 step (3) influence of refining adjustment of crude Fluvoxamine maleate to different pH on yield and quality of Fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust to different pH values, natural cooling is carried out, the temperature is reduced to 10-15 ℃, stirring is continued for 0.5h, filtration is carried out, and ice water is used for washing filter cakes. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The effect of refining and adjusting the crude product of fluvoxamine maleate to different pH values on the yield and quality of fluvoxamine maleate in the step (3) is shown in Table 10.
Table 10
| Sequence number | pH | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | 5.3～5.5 | 89.2 | 99.98 | Not detected |
| 2 | 5.0～5.2 | 84.6 | 99.90 | 0.06 |
| 3 | 5.7～6.0 | 85.6 | 99.85 | 0.07 |
Experimental results show that the target product can be obtained by adjusting the pH to the above value, and the factors such as the comprehensive yield, the quality and the like are obtained, wherein the effect is optimal when the pH value is 5.3-5.5.
Example 11 step (3) refining of crude fluvoxamine maleate different crystallization temperatures influence on yield and quality of fluvoxamine maleate
(1) 80g of n-butanol is added into a 1000mL three-necked flask, stirring is started, 10.4g of sodium hydroxide is added, heating is carried out to 30-35 ℃, sha Mingwo 20.0.0 g of fluvone is added, and 9.8g of 2-chloroethylamine hydrochloride/20 g of water mixed solution is dropwise added into the reaction solution. And (3) reacting for 2h at 30-35 ℃.
(2) After the reaction, 40g of water is added, the mixture is stirred for 10min, 8.5g of maleic acid is added into the organic phase, and the mixture is stirred for 2.5h at 20-30 ℃.
(3) 160g of water is added, the temperature is raised to 40-45 ℃, sodium carbonate is added to adjust the pH value to 5.3-5.5, natural cooling is carried out, the temperature is reduced to a certain temperature, stirring is continued for 0.5h, filtration is carried out, and the filter cake is washed by ice water. And drying to obtain fluvoxamine maleate.
The detection method comprises the following steps: high performance liquid chromatography
The method comprises the following steps: chp 2020-related substances detection method
The influence of different crystallization temperatures on the yield and quality of the fluvoxamine maleate obtained by refining the fluvoxamine maleate crude product in the step (3) is shown in table 11.
TABLE 11
| Sequence number | Temperature (. Degree. C.) | Yield (%) | Purity (%) | Impurity F content (%) |
| 1 | 3～8 | 90.3 | 99.25 | 0.10 |
| 2 | 10～15 | 89.2 | 99.98 | Not detected |
| 3 | 25～30 | 66.0 | 99.98 | Not detected |
Experimental results show that the target product can be obtained in the temperature range of 3-30 ℃ in the step (3), and the factors such as the comprehensive yield and quality can be obtained, wherein the optimal condition is 10-15 ℃.
Claims (6)
1. The preparation method of fluvoxamine maleate is characterized by adopting a one-pot method to synthesize the fluvoxamine maleate, and comprises the following specific steps of:
(1) N-hydroxy-5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentaneimine and 2-chloroethylamine hydrochloride take N-butanol as a solvent, and perform substitution reaction under the existence of sodium hydroxide to obtain fluvoxamine free base, wherein the reaction temperature is 30-35 ℃, and the molar ratio of fluvoxamine oxime to 2-chloroethylamine hydrochloride to sodium hydroxide is 1:1.05:3.5;
(2) Adding water into the reaction liquid in the step (1), separating the liquid, and adding maleic acid into an organic phase to form salt to prepare a crude product of fluvoxamine maleate;
(3) And (3) adding water into the crude product of fluvoxamine maleate obtained in the step (2), heating to dissolve, adjusting the pH to 5.0-6.0 by using sodium carbonate, and cooling and crystallizing to obtain fluvoxamine maleate.
2. The preparation method of claim 1, wherein the molar ratio of maleic acid to N-hydroxy-5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentaneimine in the step (2) is 0.9-1.4:1, and the salt formation temperature of fluvoxamine free base and maleic acid is 5-45 ℃.
3. The preparation method of claim 2, wherein the molar ratio of maleic acid to N-hydroxy-5-methoxy-1- [4- (trifluoromethyl) phenyl ] -1-pentaneimine in the step (2) is 1.0:1, and the salt formation temperature of fluvoxamine free base and maleic acid is 20-30 ℃.
4. The method according to claim 1, wherein the dissolution temperature in the step (3) is 40-55 ℃, and the crystallization temperature is 3-30 ℃.
5. The method according to claim 4, wherein the dissolution temperature in the step (3) is 40-45 ℃ and the crystallization temperature is 10-15 ℃.
6. The method according to claim 1, wherein the pH in the step (3) is 5.3 to 5.5.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6433225B1 (en) * | 1999-11-12 | 2002-08-13 | Sun Pharamaceutical Industries, Ltd. | Process for the preparation of fluvoxazmine maleate |
| CN101654419A (en) * | 2009-09-12 | 2010-02-24 | 西北师范大学 | Preparation method of fluvoxamine maleate |
| CN104703967A (en) * | 2012-08-29 | 2015-06-10 | 爱斯泰克医药有限公司 | Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same |
| CN116023296A (en) * | 2022-12-29 | 2023-04-28 | 上海国创医药股份有限公司 | Preparation method of fluvoxamine maleate |
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| US6433225B1 (en) * | 1999-11-12 | 2002-08-13 | Sun Pharamaceutical Industries, Ltd. | Process for the preparation of fluvoxazmine maleate |
| CN101654419A (en) * | 2009-09-12 | 2010-02-24 | 西北师范大学 | Preparation method of fluvoxamine maleate |
| CN104703967A (en) * | 2012-08-29 | 2015-06-10 | 爱斯泰克医药有限公司 | Method for purifying fluvoxamine free base and method for preparing highly pure fluvoxamine maleate using same |
| CN116023296A (en) * | 2022-12-29 | 2023-04-28 | 上海国创医药股份有限公司 | Preparation method of fluvoxamine maleate |
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