CN114478271A - Preparation method of desvenlafaxine succinate - Google Patents
Preparation method of desvenlafaxine succinate Download PDFInfo
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- CN114478271A CN114478271A CN202111515317.5A CN202111515317A CN114478271A CN 114478271 A CN114478271 A CN 114478271A CN 202111515317 A CN202111515317 A CN 202111515317A CN 114478271 A CN114478271 A CN 114478271A
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- venlafaxine
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- 229960004981 desvenlafaxine succinate Drugs 0.000 title claims abstract description 19
- PWPDEXVGKDEKTE-UHFFFAOYSA-N butanedioic acid;4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol;hydrate Chemical compound O.OC(=O)CCC(O)=O.C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 PWPDEXVGKDEKTE-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960004688 venlafaxine Drugs 0.000 claims abstract description 28
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960001623 desvenlafaxine Drugs 0.000 claims abstract description 8
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000004537 pulping Methods 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 3
- 239000012535 impurity Substances 0.000 claims abstract description 3
- 239000001384 succinic acid Substances 0.000 claims abstract description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 239000012065 filter cake Substances 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000002535 acidifier Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLWCNZQVNYRELK-UHFFFAOYSA-N dodecane-1-thiol;sodium Chemical compound [Na].CCCCCCCCCCCCS YLWCNZQVNYRELK-UHFFFAOYSA-N 0.000 claims 1
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000010304 firing Methods 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 1
- 230000001335 demethylating effect Effects 0.000 abstract 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- OVYQSRKFHNKIBM-UHFFFAOYSA-N butanedioic acid Chemical compound OC(=O)CCC(O)=O.OC(=O)CCC(O)=O OVYQSRKFHNKIBM-UHFFFAOYSA-N 0.000 description 3
- 238000005119 centrifugation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- WNAHIZMDSQCWRP-UHFFFAOYSA-N dodecane-1-thiol Chemical compound CCCCCCCCCCCCS WNAHIZMDSQCWRP-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- SXDQRQUWNQKZBL-UHFFFAOYSA-N butanedioic acid;hydrate Chemical compound O.OC(=O)CCC(O)=O SXDQRQUWNQKZBL-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- -1 desvenlafaxine succinate compound Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 229940127221 norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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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 discloses a preparation method of desvenlafaxine succinate bulk drug with firing residue less than 0.1% in high yield, which comprises the steps of reacting venlafaxine under a demethylating reagent, acidifying to pH1.0-4.0, extracting impurities by using an organic solvent, adjusting the pH of a system to 9.0-10.0 by using alkali at 20.0-50.0 ℃, centrifuging, pulping by using water until the firing residue of desvenlafaxine is less than or equal to 0.1%, and salifying a wet product with succinic acid in acetone water. The preparation method disclosed by the invention has the advantages of high yield and strong production operability, and can realize large-scale production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of desvenlafaxine succinate bulk drug.
Background
Desvenlafaxine succinate is a new antidepressant drug in the class of 5-hydroxytryptamine-norepinephrine reuptake inhibitors developed by huh. The invention patent CN1501909A of original research company discloses a preparation method of desvenlafaxine succinate compound, which comprises the following steps: venlafaxine (55g), dodecyl mercaptan, sodium ethoxide in ethanol was added to a pressurized vessel, the temperature was raised to 150 ℃ and the reaction mixture was stirred for 2 days, then the temperature was lowered and the solution was filtered, the pH of the filtrate was adjusted to 9.5 with aqueous hydrogen chloride solution, suction filtration was carried out, the filter cake was washed with ethanol and dried under vacuum to give 42g of free base with a yield of 80.43%. Another example is to use dodecyl mercaptan (122g), venlafaxine and sodium methoxide in methanol, solvent PEG400 heated to 190 ℃, distill off methanol and stir at 190 ℃ for reaction for 2 hours, then cool and add 2-propanol (450g), adjust pH to 9.5 with hydrochloric acid aqueous solution, filter cake washed with 2-propanol, toluene, 2-propanol and water, get venlafaxine, the yield is 82.5%. The yield of the desvenlafaxine to succinate monohydrate in acetone and water is 85.8 percent at most, the yield of the two-step latrine is 70.8 percent at most, and the latrine yield is low; the alkalization temperature of mass production is controlled to be 0-10 ℃, the pH value is adjusted to be 9-10, centrifugation is difficult, and percolation exists, so that a large amount of salt is remained in a desvenlafaxine filter cake, finally, the burning residues of the raw material medicines are higher than the pharmacopoeia standard and cannot exceed the requirement of 0.1%, and industrialization is difficult to realize.
Disclosure of Invention
The invention aims to provide a method for preparing desvenlafaxine succinate bulk drug with high yield and capable of producing and amplifying prepared burning residues which meet pharmacopoeia requirements (which are not more than 0.1%).
The invention provides a preparation method for preparing desvenlafaxine succinate with high yield, which comprises the following steps:
step 1: venlafaxine reacts with sodium dodecyl mercaptide to prepare a desvenlafaxine reaction solution;
step 2: adjusting the pH of the reaction solution to 1.0-4.0 by using an acidifying reagent, and extracting impurities which do not form salt by using an organic solvent;
and step 3: controlling the temperature of the water phase obtained in the step 2 to be 20-50 ℃, and adjusting the pH value to be 9.0-10.0 by using an alkalizer;
and 4, step 4: centrifuging the system after alkalization in the step 3, detecting the burning residues in filter cakes, and pulping the filter cakes by using water if the content of the burning residues in the filter cakes is more than 0.1% until the content of the burning residues in the centrifugal filter cakes is not more than 0.1%;
and 5: and (4) directly feeding the desvenlafaxine wet product prepared in the step (4), adding an acetone aqueous solution and succinic acid, heating to dissolve, cooling, filtering, and drying under reduced pressure and vacuum to obtain the desvenlafaxine succinate bulk drug.
In the above embodiment of the present invention, the reaction described in step 1 is carried out in N-methylpyrrolidone; optionally, the ratio of N-methylpyrrolidone to venlafaxine is (2ml to 5ml):1g, preferably 3ml:1 g.
In the above embodiment, the molar ratio of venlafaxine to sodium dodecyl mercaptide in step 1 is 1 (2-4), preferably 1: 3.5.
In the above embodiment, the acidifying agent in step 2 is hydrochloric acid.
In the above embodiment, the organic solvent in step 2 is ethyl acetate or dichloromethane.
In the above embodiment, the alkalizing agent in step 3 is sodium hydroxide, potassium carbonate or sodium carbonate.
In the above embodiment, the temperature control in step 3 is 20 ℃ to 30 ℃ or 40 ℃ to 50 ℃.
In the above embodiment, the weight ratio of succinic acid in step 4 to venlafaxine in step 1 is 0.37: 1.
In the above embodiment, the ratio of acetone in the aqueous acetone solution in step 4: the volume ratio of water was 2.5: 1.
In the above embodiment, the temperature for the temperature-raising dissolution in the step 5 is 45 ℃ to 70 ℃, preferably 55 ℃ to 65 ℃.
In the above embodiment, the temperature reduction in step 4 is: rapidly cooling to 30-40 ℃, and keeping the temperature at 30-40 ℃ for stirring and crystallizing for about 2 hours; then cooling to 5 ℃, stirring and crystallizing for 2 h.
The beneficial results of the invention are:
the preparation method of desvenlafaxine succinate provided by the invention has the advantages that the latrine yield is 85.0% (calculated from venlafaxine) which is higher than that of the two-step highest latrine yield of 70.8% reported in patent CN1501909A, and meanwhile, the invention solves the technical problem of how to prepare qualified desvenlafaxine succinate bulk drug on large-scale production.
Detailed Description
The following examples further illustrate the invention, but the scope of the invention is not limited thereto.
Comparative example preparation of desvenlafaxine succinate
Adding 92.22kg of venlafaxine, sodium dodecyl mercaptide (3.5eq) and N-methylpyrrolidone (3.0ml/g) into a reaction kettle, stirring and heating to 170-180 ℃, keeping the temperature and stirring for reaction for 6 hours, cooling to below 50 ℃, adding water (5ml/g) and ethyl acetate (4ml/g), controlling the temperature to be 0-10 ℃, adjusting the pH to 1 by using concentrated hydrochloric acid, separating liquid, washing the water phase by using ethyl acetate (4ml/g), controlling the temperature of the water phase to be 0-10 ℃, dropwise adding 40% sodium hydroxide aqueous solution to adjust the pH to 9-10, filtering, obtaining a wet desvenlafaxine product with the weight of 91.18(kg) and the water content of 13.8kg, wherein the particle size of the product is smaller, the centrifugation is difficult, and the penetration filtration, the filter cake is viscous and the pulping is difficult.
Adding 91.18(kg) of wet desmethylvenlafaxine into a reaction kettle, sequentially adding 0.37g/g of succinic acid (succinic acid) (calculated by the dosage of venlafaxine), 5.27g/g of acetone (calculated according to 100% theoretical yield of desmethylvenlafaxine), and 2.61m-X kg of purified water, (m is 92.22kg of the dosage of venlafaxine, and X is 91.18kg of the weight of the wet desmethylvenlafaxine), stirring, heating to 55-65 ℃, after the system is dissolved, carrying out heat filtration, stirring, heating to 55-65 ℃, quickly cooling to 30-40 ℃, carrying out heat preservation, stirring and crystallizing at 30-40 ℃ for about 2 hours. Then cooling to 5 ℃, stirring and crystallizing for 2 h. Filtering, drying the filter cake at 45-55 ℃ under reduced pressure for 10h to obtain 109.7kg of white-like to white crystalline powder with the yield of 76.9 percent and the burning residue of 3.8 percent;
unqualified residues and reworking: adding 90.14kg of desvenlafaxine succinate obtained in the previous step into a reaction kettle, adding 3.55g/g of acetone and 1.42g/g of purified water, heating to 55.0-65.0 ℃, cooling to-10.0-5 ℃, stirring for 2.0-3.0 h, centrifuging, drying a filter cake at 50.0-60.0 ℃ and a vacuum degree not lower than-0.08 MPa under reduced pressure until the water content is qualified, obtaining 80.02kg, obtaining a yield of 88.77%, detecting the burned residues by 3.5%, and determining the standard limit of 0.1%, which is not qualified;
and (3) pulping and reworking only by using water again: 77.02kg of desvenlafaxine succinate is added into a reaction kettle, 6.0g/g of water is added, the mixture is pulped for 6 hours +/-10 minutes at the temperature of 20.0-30.0 ℃, the filter cake is washed by 1.58g/g of acetone after centrifugation, and the filter cake is decompressed and dried at the temperature of 50.0-60.0 ℃ and the vacuum degree of not less than-0.08 MPa until the water content is qualified, so that 50.05kg of desvenlafaxine succinate is obtained, the yield is 64.96 percent, and the residues left after ignition are 0.02 percent.
Example 1 preparation of desvenlafaxine succinate
Adding 89.62kg of venlafaxine, sodium dodecyl sulfate (3.5eq) and N-methylpyrrolidone (3.0ml/g) into a reaction kettle, stirring and heating to 170-180 ℃, keeping the temperature and stirring for reaction for 6 hours, cooling to below 50 ℃, adding water (5ml/g) and ethyl acetate (4ml/g), controlling the temperature to be 0-10 ℃, adjusting the pH to 1 by using concentrated hydrochloric acid, separating liquid, washing the water phase by using ethyl acetate (4ml/g), controlling the temperature of the water phase to be 20-30 ℃, dropwise adding 40% sodium hydroxide aqueous solution to adjust the pH to 9-10, filtering, detecting 2.5% of burning residues on a filter cake, detecting 6.8g/g of the filter cake by using purified water, pulping at 20-30 ℃ for 0.5-1.0 hour, centrifuging, detecting 0.06% of the burning residues on the filter cake, obtaining a wet venlafaxine product, weighing 115.33(kg), and containing water
Wherein m is 89.62kg of venlafaxine feeding amount.
115.33(kg) of wet desmethylvenlafaxine is added into a reaction kettle, and then 0.37g/g of succinic acid (succinic acid) (calculated by the dose of venlafaxine), 5.27g/g of acetone (calculated according to 100% theoretical yield of desmethylvenlafaxine), 2.61m-X g of purified water (m is 89.62kg of venlafaxine, and X is 115.33 of the weight of the wet desmethylvenlafaxine) are added in sequence, stirred, heated to 55-65 ℃, the system is heated to be clear, then filtered by heat, rapidly cooled to 30-40 ℃, kept at 30-40 ℃, stirred and crystallized for about 2 hours. Then cooling to 5 ℃, stirring and crystallizing for 2 h. Filtering, drying the filter cake at 45-55 deg.C under reduced pressure for 10h to obtain white-like to white crystalline powder 109.7kg with yield of 85.0% and residue on ignition 0.02% (calculated from venlafaxine).
Example 2 preparation of desvenlafaxine succinate
Adding 85.12kg of venlafaxine, sodium dodecyl mercaptide (3.5eq) and N-methylpyrrolidone (3.0ml/g) into a reaction kettle, stirring and heating to 170-180 ℃, keeping the temperature and stirring for reaction for 6 hours, cooling to below 50 ℃, adding water (5ml/g) and ethyl acetate (4ml/g), controlling the temperature to be 0-10 ℃, adjusting the pH to be 4 by using concentrated hydrochloric acid, separating liquid, washing the water phase by using dichloromethane (4ml/g), controlling the temperature of the water phase to be 40-50 ℃, dropwise adding 40% sodium hydroxide aqueous solution to adjust the pH to be 9-10, filtering, detecting 2.7% of burning residues on a filter cake, using 6.8g/g of purified water on the filter cake, pulping at 20-30 ℃ for 0.5-1.0 hour, centrifuging, detecting 0.05% of the burning residues on the filter cake, obtaining a wet venlafaxine product, weighing 108.11(kg), and containing water
Wherein m is 85.12kg of venlafaxine feeding amount.
108.11(kg) of wet desmethylvenlafaxine is added into a reaction kettle, and then 0.37g/g of succinic acid (succinic acid) (calculated by the dose of venlafaxine), 5.27g/g of acetone (calculated according to 100% theoretical yield of desmethylvenlafaxine), 2.61m-X (m is 85.12kg of venlafaxine, and X is 108.11kg of wet desmethylvenlafaxine) and 2.61m-X of purified water are sequentially added into the reaction kettle, stirred and heated to 55-65 ℃, and after the system is dissolved, the mixture is thermally filtered, rapidly cooled to 30-40 ℃, and kept at 30-40 ℃ for stirring and crystallizing for about 2 hours. Then cooling to 5 ℃, stirring and crystallizing for 2 h. Filtering, drying the filter cake at 45-55 deg.C under reduced pressure for 10h to obtain 107.90kg of white-like to white crystalline powder with yield of 88.0% and 0.01% of residue on ignition (calculated from venlafaxine).
Finally, it is noted that the above-mentioned embodiments illustrate rather than limit the invention, and that, while the invention has been described with reference to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A preparation method of desvenlafaxine succinate comprises the following steps:
step 1: venlafaxine reacts with sodium dodecyl mercaptan to prepare a desvenlafaxine reaction solution;
step 2: adjusting the pH of the reaction solution to 1.0-4.0 by using an acidifying reagent, and extracting impurities which do not form salt by using an organic solvent;
and step 3: controlling the temperature of the water phase obtained in the step 2 to be 20-50 ℃, and adjusting the pH value to be 9.0-10.0 by using an alkalizer;
and 4, step 4: centrifuging the system after alkalization in the step 3, detecting the burning residues in filter cakes, and pulping the filter cakes by using water if the content of the burning residues in the filter cakes is more than 0.1% until the content of the burning residues in the centrifugal filter cakes is not more than 0.1%;
and 5: and (4) directly feeding the desvenlafaxine wet product prepared in the step (4), adding an acetone aqueous solution and succinic acid, heating to dissolve, cooling, filtering, and drying under reduced pressure and vacuum to obtain the desvenlafaxine succinate bulk drug.
2. The process according to claim 1, wherein the reaction in step 1 is carried out in N-methylpyrrolidone, optionally in a ratio of N-methylpyrrolidone to venlafaxine of (2 ml-5 ml):1g, preferably 3ml:1 g.
3. The preparation method of claim 1, wherein the molar ratio of venlafaxine to sodium dodecyl mercaptide in step 1 is 1 (2-4), preferably 1: 3.5.
4. The method according to claim 1, wherein the acidifying agent in step 2 is hydrochloric acid.
5. The method according to claim 1, wherein the organic solvent used in step 2 is ethyl acetate or dichloromethane.
6. The method according to claim 1, wherein the alkalizer in the step 3 is sodium hydroxide, potassium carbonate or sodium carbonate.
7. The method according to claim 1, wherein the temperature control in step 3 is 20-30 ℃ or 40-50 ℃.
8. The production method according to any one of claims 1 to 7, wherein the ratio of acetone in the aqueous acetone solution in step 4: the volume ratio of water was 2.5: 1.
9. The method of any one of claims 1 to 7, wherein the weight ratio of succinic acid in step 4 to venlafaxine in step 1 is 0.37: 1.
10. The production method according to any one of claims 1 to 7, wherein the temperature for the temperature-elevating dissolution in step 5 is 45 ℃ to 70 ℃, preferably 55 ℃ to 65 ℃.
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| CN202111515317.5A CN114478271B (en) | 2021-12-13 | 2021-12-13 | Preparation method of desmethylvenlafaxine succinate |
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| US20080015259A1 (en) * | 2006-04-17 | 2008-01-17 | Valerie Niddam-Hildesheim | Substantially pure O-desmethylvenlafaxine and processes for preparing it |
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