CN116640104B - Industrial synthesis method of telithromycin - Google Patents
Industrial synthesis method of telithromycin Download PDFInfo
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- CN116640104B CN116640104B CN202310592582.6A CN202310592582A CN116640104B CN 116640104 B CN116640104 B CN 116640104B CN 202310592582 A CN202310592582 A CN 202310592582A CN 116640104 B CN116640104 B CN 116640104B
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- chlorophenyl
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- telithromycin
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- piperidine
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- LJVAJPDWBABPEJ-PNUFFHFMSA-N telithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)[C@@H](C)C(=O)O[C@@H]([C@]2(OC(=O)N(CCCCN3C=C(N=C3)C=3C=NC=CC=3)[C@@H]2[C@@H](C)C(=O)[C@H](C)C[C@@]1(C)OC)C)CC)[C@@H]1O[C@H](C)C[C@H](N(C)C)[C@H]1O LJVAJPDWBABPEJ-PNUFFHFMSA-N 0.000 title claims abstract description 20
- 229960003250 telithromycin Drugs 0.000 title claims abstract description 20
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims abstract description 22
- ZHBIWFGGIKFSHZ-UHFFFAOYSA-N 3-(4-chlorophenyl)propan-1-ol Chemical compound OCCCC1=CC=C(Cl)C=C1 ZHBIWFGGIKFSHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- OVXYDNVSUOXGQG-UHFFFAOYSA-N 1-(3-bromopropyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CCCBr)C=C1 OVXYDNVSUOXGQG-UHFFFAOYSA-N 0.000 claims abstract description 18
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 claims abstract description 13
- XLFKECRRMPOAQS-UHFFFAOYSA-N 1-[3-[3-(4-chlorophenyl)propoxy]propyl]piperidine;hydrochloride Chemical compound Cl.C1=CC(Cl)=CC=C1CCCOCCCN1CCCCC1 XLFKECRRMPOAQS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 10
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- 238000005576 amination reaction Methods 0.000 claims abstract description 7
- 238000006266 etherification reaction Methods 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 5
- 238000010189 synthetic method Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000004821 distillation Methods 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000007789 gas Substances 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- YWDQMQUSUGZXMK-UHFFFAOYSA-N methyl 3-(4-chlorophenyl)propanoate Chemical group COC(=O)CCC1=CC=C(Cl)C=C1 YWDQMQUSUGZXMK-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 6
- 239000001257 hydrogen Substances 0.000 abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 6
- 231100000024 genotoxic Toxicity 0.000 abstract description 5
- 230000001738 genotoxic effect Effects 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 3
- 229940017219 methyl propionate Drugs 0.000 abstract 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- NPANKSZVBOAPFP-UHFFFAOYSA-N 3-(4-chlorophenyl)propyl methanesulfonate Chemical compound CS(=O)(=O)OCCCC1=CC=C(Cl)C=C1 NPANKSZVBOAPFP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000009987 spinning Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- KJVMERDIXJPPRF-UHFFFAOYSA-N 1,4-dioxane;piperidine Chemical compound C1CCNCC1.C1COCCO1 KJVMERDIXJPPRF-UHFFFAOYSA-N 0.000 description 1
- TXAWBKBMGZKBNN-UHFFFAOYSA-N 1-(4-chlorophenyl)propan-1-ol Chemical compound CCC(O)C1=CC=C(Cl)C=C1 TXAWBKBMGZKBNN-UHFFFAOYSA-N 0.000 description 1
- YIJAXVWJZJYWPI-UHFFFAOYSA-N 1-piperidin-1-ylpropan-1-ol Chemical compound CCC(O)N1CCCCC1 YIJAXVWJZJYWPI-UHFFFAOYSA-N 0.000 description 1
- BBSLOKZINKEUCR-UHFFFAOYSA-N 3-(4-chlorophenyl)propanoic acid Chemical compound OC(=O)CCC1=CC=C(Cl)C=C1 BBSLOKZINKEUCR-UHFFFAOYSA-N 0.000 description 1
- 208000001573 Cataplexy Diseases 0.000 description 1
- 208000007590 Disorders of Excessive Somnolence Diseases 0.000 description 1
- 229940115480 Histamine H3 receptor antagonist Drugs 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000003395 histamine H3 receptor antagonist Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 229940125425 inverse agonist Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 201000003631 narcolepsy Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- GFBWCGULHCGLJT-UHFFFAOYSA-N oxolane;piperidine Chemical compound C1CCOC1.C1CCNCC1 GFBWCGULHCGLJT-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
Abstract
The invention discloses a synthetic method of telithromycin, which comprises the following steps: (1) 3- (4-chlorophenyl) methyl propionate undergoes a reduction reaction under the action of a reducing agent to obtain 3- (4-chlorophenyl) propanol; (2) 3- (4-chlorophenyl) propanol and 1, 3-dibromopropane are subjected to etherification reaction under the action of alkali and a phase transfer catalyst to obtain 1-bromo-3- (4-chlorophenyl) propane; (3) The 1-bromo-3- (4-chlorophenyl) propane and piperidine undergo amination reaction, and after the reaction is finished, 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained through post-treatment. The synthesis method avoids the use of a metal hydrogen reagent NaH and a potential genotoxic reagent methane sulfonate, has higher yield, and can conveniently recycle and reuse excessive reaction reagents.
Description
Technical Field
The invention relates to an industrial preparation method of histamine H3 receptor antagonist telithromycin, belonging to the technical field of pharmaceutical synthesis industrial amplification.
Background
Telithromycin is a drug for the treatment of excessive daytime sleepiness or cataplexy associated with narcolepsy, developed by bioprjet-Biotech corporation, and marketed as FDA approval in 2019. The chemical structural formula is shown in the specification, and the chemical name is 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride, and the compound is a selective histamine 3 (H3) receptor antagonist/inverse agonist. Its mechanism of action is to increase histamine synthesis and release to wake up the neurotransmitter. The preparation has the characteristics of oral administration, strong effect, small side effect and the like, and has optimistic market application prospect.
In the currently published synthetic method of telithromycin, the common problems are that raw material reagents are expensive, not easy to obtain and high in cost; the synthesis process can introduce genotoxic impurities or can use a catalyst with high toxicity; the synthesis method has long steps and complex operation, and all the factors are unfavorable for the scale-up production.
In the synthesis methods disclosed in documents WO2007006708 and CN 103435575A, 3- (4-chlorophenyl) propyl methanesulfonate is used as a key intermediate, and the intermediate is prepared from the highly toxic substance methanesulfonyl chloride, and the use of 3- (4-chlorophenyl) propyl methanesulfonate is extremely easy to introduce genotoxic impurities, thereby being unfavorable for the production and safe use of medicaments, and a metal hydrogen reagent NaH is used in the synthesis process, so that the safety is poor and the safe production is unfavorable.
The synthetic route is shown in the following formula:
patent CN 114014825A takes 3- (4-chlorophenyl) propionic acid as a starting material, and the 3- (piperidine) -propyl-4-chlorophenyl propionate is obtained by directly carrying out esterification reaction with 1-piperidinopropanol under the catalysis of acid, and then the telithromycin is obtained by two-step reduction reaction. The reaction condition of the reduction reaction is harsh, the price of the reaction reagent is high, the reaction reagent is not easy to be amplified to industrial production, and the yield is not high in the implementation case. The synthetic route is shown in the following formula:
patent CN 104447620B takes piperidine and 1, 3-dihalopropane as starting materials, and performs condensation, etherification and then reacts with hydrochloric acid to obtain telithromycin. The ratio of piperidine to 1, 3-dihalide used in the embodiment is 2:3, the problems are mainly that the reaction selectivity is poor, impurities of piperidine groups on quaternary ammonium salt or dihalide are easy to generate, a metal hydrogen reagent NaH is also used as alkali in the ether-forming process, the ignition is easy to happen in production, the safety is poor, and the safety production is not facilitated.
Disclosure of Invention
The invention provides an industrial synthesis method of telithromycin, which avoids the use of a metal hydrogen reagent NaH and a potential genotoxic reagent methane sulfonate, has higher yield and is more suitable for industrialization.
The technical scheme of the invention is as follows:
a synthetic method of telithromycin, comprising the following steps:
(1) Carrying out reduction reaction on the 3- (4-chlorophenyl) propionic acid alkyl ester under the action of a reducing agent to obtain 3- (4-chlorophenyl) propanol;
(2) 3- (4-chlorophenyl) propanol and 1, 3-dibromopropane are subjected to etherification reaction under the action of alkali and a phase transfer catalyst to obtain 1-bromo-3- (4-chlorophenyl) propane;
(3) The 1-bromo-3- (4-chlorophenyl) propane and piperidine undergo amination reaction, and after the reaction is finished, 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained through post-treatment.
The reaction formula is as follows (for example, methyl 3- (4-chlorophenyl) propionate):
preferably, in the step (1), the alkyl 3- (4-chlorophenyl) propionate is methyl 3- (4-chlorophenyl) propionate, ethyl 3- (4-chlorophenyl) propionate, propyl 3- (4-chlorophenyl) propionate;
the reducing agent is NaBH 4 ；
The reduction reaction is carried out in an alcohol solvent, and the alcohol is one or a mixture of ethanol, isopropanol and tertiary butanol.
Preferably, in the step (1), the temperature of the reduction reaction is 30 to 50 ℃ and the reaction time is 5 to 10 hours.
The selection of the phase transfer catalyst in the step (2) has a great influence on the reaction result, and preferably, in the step (2), the phase transfer catalyst is tetrabutylammonium bromide (TBAB) or tetrabutylammonium iodide;
the alkali is KOH.
As a further preferred aspect, the phase transfer catalyst is tetrabutylammonium bromide (cheaper than tetrabutylammonium iodide), and the base is powdered KOH, and the reaction yield is higher.
Preferably, in the step (2), the molar ratio of the 3- (4-chlorophenyl) propanol to the 1, 3-dibromopropane is 1:2.0-5.0.
Preferably, in the step (2), the reaction temperature is 50-60 ℃ and the reaction time is 10-15 h.
Preferably, in the step (2), the etherification reaction is carried out in an ether solvent, wherein the ether solvent is tetrahydrofuran or 1, 4-dioxane.
Preferably, in the step (3), in the step (2), the molar ratio of the 1-bromo-3- (4-chlorophenyl) propane to the piperidine is 1:4.0-10.0.
Preferably, in the step (3), the amination is performed in an ether solvent, wherein the ether solvent is tetrahydrofuran or 1, 4-dioxane.
Preferably, in the step (3), after the amination reaction is finished, the post-treatment process is as follows:
filtering out generated salt, spin drying filtrate, recovering tetrahydrofuran or dioxane solution of piperidine, adding water and methylene dichloride into the obtained residue for liquid-separating extraction, washing an organic phase by water and saturated saline water respectively, then removing methylene dichloride through reduced pressure distillation, adding ethanol, introducing hydrogen chloride gas into the ethanol to form salt, and crystallizing by heating and cooling to obtain the 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride.
Compared with the prior art, the invention has the beneficial effects that:
the process steps are simple, and three steps of reactions are carried out; the reaction condition is mild, the use of a metal hydrogen reagent NaH and a potential genotoxic reagent methane sulfonate is avoided, and the reaction condition is safe; raw materials are easy to obtain, and the price is low; in the second and third steps, excessive reactants inhibit side reactions, and simultaneously, the recovery is conveniently realized by distillation and recovery, so that the yield can be greatly improved and the cost can be reduced.
Detailed Description
Example 13 Synthesis of (4-chlorophenyl) propanol
76g (2.0 mol) of NaBH 4 To 3500mL of t-butanol, the temperature was raised to 40℃and stirred. A mixture of 700g (3.5 mol) of methyl 3- (4-chlorophenyl) propionate and 600mL of methanol was added dropwise, and the mixture was reacted at 40-45℃for 8 hours. After the reaction is finished, the temperature is reduced to 0 ℃, 200mL of 6N hydrochloric acid is added dropwise for quenching, and the mixture is stirred for 30min at room temperature after the addition is finished. The temperature is controlled below 70 ℃ and the tertiary butanol and the methanol are distilled under reduced pressure, 1000mL of water and 2000mL of methylene dichloride are added for liquid-separating extraction after the distillation is finished, the organic phase is respectively washed by 1000mL of 1N NaOH aqueous solution and 1000mL of saturated sodium chloride aqueous solution, 570g of light yellow oily matter is obtained after the distillation of the organic phase is finished, and the yield is: 95.1%.
Example 2: synthesis of 1-bromo-3- (4-chlorophenyl) propane
340g (2.0 mol,1.0 eq) of 3- (4-chlorophenyl) propanol, 17g of TBAB and 1700mL of THF are added into a 5.0L reaction flask, 843g (4.0 mol,2.0 eq) of 1, 3-dibromopropane are added, 168g (3.0 mol,1.5 eq) of KOH are added into the reaction solution, the temperature is raised to 50-60 ℃ after the addition, the reaction is carried out for 12 hours, and the residual amount of 3- (4-chlorophenyl) propanol serving as a reaction raw material is monitored by a sampling liquid phase to be less than 3%. After the reaction is finished, the temperature is reduced to 0 ℃, 220mL of 6N hydrochloric acid is added dropwise for quenching, and the mixture is stirred for 30min at room temperature after the addition is finished. THF was distilled off under reduced pressure at a temperature of 70℃or below, and after the distillation was completed, 500mL of water and 1500mL of methylene chloride were added to extract. After washing with 500mL of saturated aqueous sodium chloride, the organic phase was distilled off to obtain methylene chloride, and excess 1, 3-dibromopropane was distilled off under reduced pressure by an oil pump to obtain 545.3g of 1-bromo-3- (4-chlorophenyl) propane in a yield: 94%.
Example 3: synthesis of 1-bromo-3- (4-chlorophenyl) propane
34g (0.2 mol,1.0 eq) of 3- (4-chlorophenyl) propanol and 170mL of THF are introduced into a 1.0L reaction flask, 84g (0.4 mol,2.0 eq) of 1, 3-dibromopropane are added, 16.8g (0.3 mol,1.5 eq) of KOH are added to the reaction mixture, and the mixture is heated to 50-60℃and reacted for 12 hours. The reaction was monitored by sample TLC and found to be still largely 3- (4-chlorophenyl) propanol as a residual starting material, and continued at 50-60℃for 12 hours, while the reaction was monitored by TLC and found to be unchanged, and still largely 3- (4-chlorophenyl) propanol as a residual starting material was not continuously treated.
Example 4: synthesis of 1-bromo-3- (4-chlorophenyl) propane
34g (0.2 mol,1.0 eq) of 3- (4-chlorophenyl) propanol, 1.7g of TBAB and 170mL of THF are introduced into a 1.0L reaction flask, 84g (0.4 mol,2.0 eq) of 1, 3-dibromopropane are added, 16.8g (0.3 mol,1.5 eq) of KOH in the form of flakes are added to the reaction mixture, and the mixture is heated to 50-60℃and reacted for 12 hours. The reaction was monitored by sampling TLC and found to have a significant amount of 3- (4-chlorophenyl) propanol remaining as a starting material, and the reaction was continued at 50-60℃for 12 hours, with the sample liquid phase monitoring the reaction starting material 3- (4-chlorophenyl) propanol remaining about 15% and no further treatment was continued.
It was found from examples 2 and 3 that TBAB plays a great role as a phase transfer catalyst in this reaction, and that 3- (4-chlorophenyl) propanol as a raw material remained relatively large in the absence of the phase transfer catalyst; the results of examples 2 and 4 show that the use of powdered potassium hydroxide works better than flaky potassium hydroxide; the use of the extremely flammable metallic hydrogen reagent NaH is avoided by the phase transfer catalyst, powdered KOH, 1, 3-dibromopropane and THF system.
Example 5: synthesis of 1-bromo-3- (4-chlorophenyl) propane
340g (2.0 mol,1.0 eq) of 3- (4-chlorophenyl) propanol, 17g of TBAB and 1700mL of dioxane were added to a 5.0L reaction flask, 2107g (10.0 mol,5.0 eq) of 1, 3-dibromopropane were added, 168g (3.0 mol,1.5 eq) of KOH was further added to the reaction mixture, the mixture was heated to 50-60℃after the addition, the reaction was carried out for 12 hours, and the residual amount of 3- (4-chlorophenyl) propanol as a reaction material was monitored by a sampling liquid phase to be less than 3%. After the reaction is finished, the temperature is reduced to 0 ℃, 220mL of 6N hydrochloric acid is added dropwise for quenching, and the mixture is stirred for 30min at room temperature after the addition is finished. THF was distilled off under reduced pressure at a temperature of 70℃or below, and after the distillation was completed, 500mL of water and 1500mL of methylene chloride were added to extract. Then, the mixture was washed with 500mL of saturated aqueous sodium chloride, the organic phase was distilled off to obtain methylene chloride by a water pump, and then, excess 1, 3-dibromopropane was distilled off under reduced pressure by an oil pump to obtain 555g of 1-bromo-3- (4-chlorophenyl) propane in a yield: 95.7%.
Example 6:1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride
291.6g (1.0 mol,1.0 eq) of 1-bromo-3- (4-chlorophenyl) propane, 340g (4.0 mol,4.0 eq) of piperidine and 580mL of THF are added into a 2.0L reaction bottle, the temperature is raised to 55-65 ℃ after the addition is finished, the reaction is carried out for 12 hours, salt precipitation occurs in the reaction process, the residual amount of the reaction raw material 1-bromo-3- (4-chlorophenyl) propane is monitored to be less than 3% in a liquid phase, the generated salt is filtered after the reaction is cooled, the filtrate is dried in a spinning mode, and the distilled tetrahydrofuran piperidine solution can be directly recycled for the next reaction. To the residue obtained by distillation, 300ml of water and 600ml of methylene chloride were added for liquid-separation extraction, and the organic phase was washed once with 300ml of water and 300ml of saturated brine, respectively. The organic phase is distilled under reduced pressure at the temperature of below 70 ℃ to obtain dichloromethane, 800ml of ethanol is added after the distillation is finished, hydrogen chloride gas is introduced to form salt, the salt is fully formed, then the mixture is heated to reflux, the temperature is gradually reduced to 0-5 ℃, 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained after filtration, 294g is obtained after drying and constant weight, and the yield is: 88% and purity 99.5%. The product characterization data are as follows: (chloroform-d) d:11.93 (s, 1H), 7.26-7.20 (m, 2H), 7.13-7.06 (m, 2H), 3.55-3.45 (m, 4H), 3.39 (t, j=6.3 hz, 2H), 3.06-2.94 (m, 2H), 2.70-2.55 (m, 4H), 2.35-2.10 (m, 4H), 1.83 (ddd, j=12.9, 8.8,5.3,2.5hz, 5H), 1.41 (qt, j=11.4, 3.1hz, 1H).
Example 7:1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride
291.6g (1.0 mol,1.0 eq) of 1-bromo-3- (4-chlorophenyl) propane, 850g (10.0 mol,10.0 eq) of piperidine and 580mL of dioxane are added into a 2.0L reaction bottle, the temperature is raised to 55-65 ℃ after the addition is finished, salt is separated out during the reaction, the residual amount of the reaction raw material 1-bromo-3- (4-chlorophenyl) propane is less than 3% during the reaction, the generated salt is filtered after the reaction is finished in a cooling way, the filtrate is dried in a spinning way, and the distilled dioxane piperidine solution can be directly reused for the next reaction. To the residue obtained by distillation, 300ml of water and 600ml of methylene chloride were added for liquid-separation extraction, and the organic phase was washed once with 300ml of water and 300ml of saturated brine, respectively. The organic phase is distilled under reduced pressure at the temperature of below 70 ℃ to obtain dichloromethane, 800ml of ethanol is added after the distillation is finished, hydrogen chloride gas is introduced to form salt, the salt is fully formed, then the mixture is heated to reflux, the temperature is gradually reduced to 0-5 ℃, 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained after filtration, 285g is obtained after drying and constant weight, and the yield is: 85.3% and purity 99.5%.
Claims (10)
1. A synthetic method of telithromycin, which is characterized by comprising the following steps:
(1) Carrying out reduction reaction on the 3- (4-chlorophenyl) propionic acid alkyl ester under the action of a reducing agent to obtain 3- (4-chlorophenyl) propanol;
the reducing agent is NaBH 4 ；
(2) 3- (4-chlorophenyl) propanol and 1, 3-dibromopropane are subjected to etherification reaction under the action of alkali and a phase transfer catalyst to obtain 1-bromo-3- (4-chlorophenyl) propane;
the phase transfer catalyst is tetrabutylammonium bromide or tetrabutylammonium iodide;
(3) The 1-bromo-3- (4-chlorophenyl) propane and piperidine undergo amination reaction, and after the reaction is finished, 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained through post-treatment.
2. The method for synthesizing telithromycin according to claim 1, wherein in the step (1), said alkyl 3- (4-chlorophenyl) propionate is methyl 3- (4-chlorophenyl) propionate, ethyl 3- (4-chlorophenyl) propionate, propyl 3- (4-chlorophenyl) propionate or butyl 3- (4-chlorophenyl) propionate;
the reduction reaction is carried out in an alcohol solvent, and the alcohol is one or a mixture of ethanol, isopropanol and tertiary butanol.
3. The method for synthesizing telithromycin according to claim 1, wherein in the step (1), the temperature of the reduction reaction is 30 to 50 ℃ and the reaction time is 5 to 10 hours.
4. The method for synthesizing telithromycin according to claim 1, wherein in the step (2), the base is KOH.
5. The method for synthesizing telithromycin according to claim 1, wherein in the step (2), the molar ratio of 3- (4-chlorophenyl) propanol to 1, 3-dibromopropane is 1:2.0-5.0;
after the reaction, the reaction was quenched, and then 1, 3-dibromopropane was recovered by distillation under reduced pressure.
6. The method for synthesizing telithromycin according to claim 1, wherein in the step (2), the reaction temperature is 50 to 60 ℃ and the reaction time is 10 to 15 hours.
7. The method for synthesizing telithromycin according to claim 1, wherein in the step (2), the etherification reaction is carried out in an ether solvent, wherein the ether solvent is tetrahydrofuran or 1, 4-dioxane.
8. The method for synthesizing telithromycin according to claim 1, wherein in step (3), the molar ratio of 1-bromo-3- (4-chlorophenyl) propane to piperidine is 1:4.0-10.0;
after the reaction, piperidine was recovered by distillation and used directly for the next reaction.
9. The method for synthesizing telithromycin according to claim 1, wherein in the step (3), the amination is performed in an ether solvent, which is tetrahydrofuran or 1, 4-dioxane.
10. The method for synthesizing telithromycin according to claim 1, wherein in the step (3), after the amination reaction is finished, distillation and dichloromethane extraction are carried out first, then dichloromethane is removed by reduced pressure distillation, ethanol is added, then hydrogen chloride gas is introduced into the ethanol for salifying, and then the 1- [3- [3- (4-chlorophenyl) propoxy ] propyl ] -piperidine hydrochloride is obtained by heating and cooling for crystallization.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103435575A (en) * | 2013-08-06 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Preparation method of 1-(3-(3-(4-chlorphenyl) propoxy) propyl) piperidine hydrochloride |
| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| WO2018082441A1 (en) * | 2016-11-01 | 2018-05-11 | 山东特珐曼药业有限公司 | Preparation method for 4-methylenepiperidine or acid addition salt thereof |
| CN109843856A (en) * | 2016-05-18 | 2019-06-04 | 米拉蒂治疗股份有限公司 | KRAS G12C inhibitor |
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| CN103435575A (en) * | 2013-08-06 | 2013-12-11 | 中国人民解放军军事医学科学院毒物药物研究所 | Preparation method of 1-(3-(3-(4-chlorphenyl) propoxy) propyl) piperidine hydrochloride |
| CN104447620A (en) * | 2014-11-28 | 2015-03-25 | 瑞阳制药有限公司 | Preparation method of 1-[3-[3-(4-chlorphenyl) propoxy] propyl]-piperidine hydrochloride |
| CN109843856A (en) * | 2016-05-18 | 2019-06-04 | 米拉蒂治疗股份有限公司 | KRAS G12C inhibitor |
| WO2018082441A1 (en) * | 2016-11-01 | 2018-05-11 | 山东特珐曼药业有限公司 | Preparation method for 4-methylenepiperidine or acid addition salt thereof |
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