CN105777745A - Preparation method of trazodone hydrochloride - Google Patents
Preparation method of trazodone hydrochloride Download PDFInfo
- Publication number
- CN105777745A CN105777745A CN201610188125.0A CN201610188125A CN105777745A CN 105777745 A CN105777745 A CN 105777745A CN 201610188125 A CN201610188125 A CN 201610188125A CN 105777745 A CN105777745 A CN 105777745A
- Authority
- CN
- China
- Prior art keywords
- preparation
- chloro
- phenyl
- trazodone
- chloropropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 229960002301 trazodone hydrochloride Drugs 0.000 title claims abstract description 33
- OHHDIOKRWWOXMT-UHFFFAOYSA-N trazodone hydrochloride Chemical compound [H+].[Cl-].ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 OHHDIOKRWWOXMT-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000003513 alkali Substances 0.000 claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 229960003991 trazodone Drugs 0.000 claims abstract description 23
- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 claims abstract description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012535 impurity Substances 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 19
- 238000010992 reflux Methods 0.000 claims description 19
- 230000000630 rising effect Effects 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- WYSGRZOBNVDTRM-UHFFFAOYSA-N C1=CC=NC=C1.O=C1C=NN=N1 Chemical compound C1=CC=NC=C1.O=C1C=NN=N1 WYSGRZOBNVDTRM-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical group CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 235000011181 potassium carbonates Nutrition 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 5
- 235000017550 sodium carbonate Nutrition 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 3
- 229940113088 dimethylacetamide Drugs 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 230000008859 change Effects 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 235000007686 potassium Nutrition 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 150000001408 amides Chemical class 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 229940035429 isobutyl alcohol Drugs 0.000 claims 1
- 239000001301 oxygen Substances 0.000 claims 1
- 229910052760 oxygen Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract 2
- NDQKGEFMUGSRNS-UHFFFAOYSA-N 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine Chemical compound C1CN(CCCCl)CCN1C1=CC=CC(Cl)=C1 NDQKGEFMUGSRNS-UHFFFAOYSA-N 0.000 abstract 1
- JVLRNANYLVRULL-UHFFFAOYSA-N 1-(3-chlorophenyl)-4-(3-chloropropyl)piperazine;hydrochloride Chemical compound [Cl-].C1CN(CCCCl)CC[NH+]1C1=CC=CC(Cl)=C1 JVLRNANYLVRULL-UHFFFAOYSA-N 0.000 abstract 1
- LJRXNXBFJXXRNQ-UHFFFAOYSA-N 2h-[1,2,4]triazolo[4,3-a]pyridin-3-one Chemical compound C1=CC=CN2C(=O)NN=C21 LJRXNXBFJXXRNQ-UHFFFAOYSA-N 0.000 abstract 1
- 238000003889 chemical engineering Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000013019 agitation Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 235000011118 potassium hydroxide Nutrition 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 230000033228 biological regulation Effects 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 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
- 239000007864 aqueous solution Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010054089 Depressive symptom Diseases 0.000 description 1
- 206010013754 Drug withdrawal syndrome Diseases 0.000 description 1
- 101000671814 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 38 Proteins 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 102100040108 Ubiquitin carboxyl-terminal hydrolase 38 Human genes 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- -1 alkyl compound Chemical class 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000024732 dysthymic disease Diseases 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention is applicable to the field of chemistry and chemical engineering and provides a preparation method of trazodone hydrochloride. The preparation method comprises the following steps: mixing N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine hydrochloride and 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one in a solvent; adding an alkali, and heating and reflowing; carrying out heat filtering into a reaction system, adding alkali liquid and heating and reflowing again in sequence; crystallizing to obtain trazodone; taking the trazodone to react with hydrochloric acid to obtain the trazodone hydrochloride. According to the preparation method of the trazodone hydrochloride, provided by the invention, the total yield of the product is improved, and the content of an impurity N-(3-chloro-phenyl)-N'-(3-chloropropyl)-piperazine is remarkably reduced, so that the industry limitation requirements can be directly met. The preparation method has simple flow steps so that the production cost is reduced; the process is stable and industrial production can be carried out.
Description
Technical field
The invention belongs to chemical field, particularly relate to the preparation method of a kind of trazodone hydrochloride.
Background technology
Trazodone hydrochloride (trazodone hydrochloride) is the derivant of triazole pyridine, mainly
Dysthymic disorder after treating depression and giving up with the anxiety neurosis of depressive symptom and drug addicts.
The side effect of this product is low, and toleration is strong, and its mechanism of action is: the first picked-up to 5-HT of suppression synaptic neural,
Thus increase 5-HT concentration in synaptic space and, with transmission information, reach antidepressant purpose.The most also demonstrate,prove
The antidepressant of real trazodone hydrochloride and anxiolytic properties can be used for treating from cocaine, benzodiazepins and
The withdrawal symptom of ethanol.Additionally, trazodone hydrochloride has obvious curative effect to improving sleep disorder.
Plurality of impurities can be attended by during preparing trazodone hydrochloride at present produce, wherein impurity alkyl compound
N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine is decided to be doubtful genotoxicity impurity, and it is quilt in USP38
Being classified as critical impurities, it is contemplated that the maximum daily dose of trazodone hydrochloride is 600mg, this impurity is defined as not
Should be more than 2.5ppm.Owing to this impurity is one of reactant synthesizing trazodone, former according to chemical reaction equilibrium
Reason, it cannot thoroughly change into trazodone, therefore control its residual and become the difficult point preparing trazodone hydrochloride
And critical process, how in trazodone hydrochloride building-up process, to control impurity N-(the chloro-phenyl of 3-)-N '-(3-chlorine third
Base) yield of-piperazine, it is provided that a kind of impurity produces the preparation method of less trazodone hydrochloride, it has also become this
Technical problem urgently to be resolved hurrily in field.
Summary of the invention
For solving above-mentioned technical problem, the invention provides the preparation method of a kind of trazodone hydrochloride, it is intended to subtract
The content preparing impurity N-in product (the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine of few trazodone hydrochloride.
The present invention is achieved in that the preparation method of a kind of trazodone hydrochloride, comprises the following steps:
N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride is mixed in a solvent with pyridine triazolone,
Add alkali, temperature rising reflux；
Reaction system is carried out successively heat filtering, adds alkali liquor temperature rising reflux again；
Crystallize, it is thus achieved that trazodone；And
By gained trazodone and hydrochloric acid reaction.
Further, described pyridine triazolone and described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloric acid
The ratio of the amount of the material of salt is 1～1.5:1.
Further, described alkali be sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate,
One in potassium bicarbonate, triethylamine, pyridine；Described alkali and described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-
The ratio of the amount of the material of piperazine hydrochloride is 2～3:1.
Further, described solvent be n-butyl alcohol, isobutanol, normal propyl alcohol, isopropanol, ethanol, methanol,
One in oxolane, 1,4-dioxane, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide；
The volume mass ratio of described solvent and described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride be 10～
30mL:1g。
Further, the product of described temperature rising reflux includes N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine, institute
The terminal stating temperature rising reflux is that HPLC detects containing of described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine
Amount is less than 0.05%.
Further, the temperature of described heat filtering is 50～75 DEG C.
Further, the concentration of described alkali liquor is 5%～20%wt；The solute of described alkali liquor be sodium hydroxide,
One in potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine.
Further, described alkali liquor is 1%～15%:1 with the volume ratio of described solvent.
Further, the temperature of described temperature rising reflux is 80～85 DEG C.
Further, the temperature of described temperature rising reflux again is 82～87 DEG C, and the time is 6～8 hours.
Further, the temperature of described crystallize is-5～15 DEG C, and the time is 1～4 hour.
Further, described preparation method the most also includes: filter, and is dried.
Further, the concentration of described hydrochloric acid is 12mol/L, and described trazodone with the condition of hydrochloric acid reaction is
By reaction system regulation to pH be 1～5.
Present invention also offers impurity N-(the chloro-phenyl of 3-)-N '-(3-chlorine third in a kind of trazodone hydrochloride preparation
Base)-piperazine content reduce method, use preparation method described above to react.
The present invention compared with prior art, has the beneficial effects that: the present invention is by improving the system of trazodone hydrochloride
Standby technique, by adjusting each response parameter in course of reaction, and adds aqueous alkali after synthetic reaction terminates
Continue reaction, carry out the operation such as temperature rising reflux and decrease temperature crystalline, make impurity N-(the chloro-phenyl of 3-)-N '-(3-chlorine
Propyl group) residual quantity of-piperazine within 2.5ppm, reached industry limit standard.The trazodone hydrochloride of the present invention
The preparation method of ketone, improves total yield of products；Streamlining step, reduces production cost；And technique
Stable, industrialized production can be carried out.
Accompanying drawing explanation
Fig. 1 is the chemical structural formula of trazodone hydrochloride prepared by the present invention.
Fig. 2 is the chemical equation preparing trazodone hydrochloride that the embodiment of the present invention provides.
Detailed description of the invention
In order to make the purpose of the present invention, technical scheme and advantage clearer, below in conjunction with accompanying drawing and reality
Execute example, the present invention is further elaborated.Only should be appreciated that specific embodiment described herein
Only in order to explain the present invention, it is not intended to limit the present invention.
Preparing trazodone hydrochloride according to technical scheme, process is as follows:
Step one: N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride is mixed with pyridine triazolone,
Add alkali, temperature rising reflux；
Step 2: reaction system is carried out successively heat filtering, adds alkali liquor temperature rising reflux again；
Step 3: crystallize, filters, and is dried, it is thus achieved that trazodone；
Step 4: by gained trazodone and hydrochloric acid reaction, it is thus achieved that trazodone hydrochloride.
Detailed process is: under room temperature, be sequentially added in reaction bulb N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-
Piperazine hydrochloride, pyridine triazolone, reaction dissolvent, start mechanical agitation, add alkali, nitrogen is protected, and rises
Temperature is to backflow, after reaction is reached home, controls temperature filtered while hot, and filtrate is added aqueous alkali, heated up back
Stream continues reaction filtrate cooling crystallize, insulation, filters, and 50 DEG C are vacuum dried to obtain faint yellow solid.
Specifically, in step one, pyridine triazolone and described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine
The ratio of the amount of the material of hydrochlorate is 1～1.5:1, preferably 1.1～1.3:1.Alkali is sodium hydroxide, hydroxide
One in potassium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine；Wherein,
The ratio of the amount of the material of alkali and described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride be 2.0～
3.0:1, preferably 2.1～2.4:1.Solvent be n-butyl alcohol, isobutanol, normal propyl alcohol, isopropanol, ethanol,
In methanol, oxolane, 1,4-dioxane, N,N-dimethylformamide or DMAC N,N' dimethyl acetamide
A kind of；Solvent and N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride volume mass ratio be 10～
30mL:1g, preferably 15～20mL:1g.
During temperature rising reflux, product includes N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine, rises
The temperature of temperature backflow is 80～85 DEG C, and the endpoint of temperature rising reflux is that HPLC detects N-(the chloro-benzene of 3-
Base) content of-N '-(3-chloropropyl)-piperazine is less than 0.05%, preferably shorter than 0.02%, and the time is generally 24～28
Hour, preferably 26 hours.
Specifically, in step 2, the temperature of heat filtering is 50～75 DEG C, preferably 60～70 DEG C.The alkali added
The concentration of liquid is 5%～20%wt, preferably 10%～15%wt；The solute of alkali liquor be sodium hydroxide, potassium hydroxide,
One in potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, preferably hydroxide
Sodium, potassium hydroxide.Wherein, alkali liquor is 1%～15%:1 with the volume ratio of described solvent, preferably 5%～10%:1.
The temperature of temperature rising reflux is 82～87 DEG C again, and the time is 6～8 hours, preferably 8 hours.
Specifically, in step 3, the temperature of crystallize is-5～15 DEG C, preferably 0～5 DEG C；Time is 1～4 hour,
Preferably 2～3 hours.Filter and carry out at normal temperatures, be dried as natural air drying.
Specifically, in step 4, the concentration of hydrochloric acid used is 12mol/L, described trazodone and hydrochloric acid reaction
Condition for by reaction system regulation to pH be 1～5, preferably 2.5～3.5.
The preparation technology of existing trazodone hydrochloride does not exist the step adding aqueous alkali to continue reaction,
Critical impurities N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine of the trazodone hydrochloride of gained remains in 100ppm
Above, if directly obtaining trazodone hydrochloride, even if purification is repeatedly without the step of independent this impurity of purification
Also it is difficult to reach the requirement of below 2.5ppm.The method of patent CN 101772490B then needs to increase song
Oxazolone or the step of trazodone hydrochloride this impurity of independent purification, although the yield that patent report is higher than 85%, but
It is that the method is relatively complicated, uses high boiling point and the solvent that is of little use；Watr-proportion is big；Use miscible with water molten
During agent, reclaim trazodone difficulty, use the operations such as azeotropic distillation, on producing during consumption energy consumption.The present invention's
Preparation method, solvent for use is relatively low, and watr-proportion is little；On the basis of trazodone customary preparation methods directly
Carry out heat filtering, add aqueous alkali temperature rising reflux operation again, the operation of improvement is combined with original technique,
Reduce energy consumption, save the time.The preparation method of the present invention solves problems of the prior art, and
Effect is notable.
Below in conjunction with comparative example and specific embodiment, the technical scheme of invention is described further.
The existing technique of comparative example 1 prepares trazodone
Toward in 2L there-necked flask under room temperature, it is sequentially added into 100g (0.323mol) N-(the chloro-phenyl of 3-)-N '-(3-
Chloropropyl)-piperazine hydrochloride, 52.4g (0.388mol) pyridine triazolone (compound ii), 1500mL is different
Propanol, starts mechanical agitation, adds 29.7g (0.743mol) sodium hydroxide, and nitrogen is protected, and is warming up to back
Stream, reacts 26 hours, and HPLC detection N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine content is 0.02%.
Control temperature is to 60～70 DEG C of heat filterings, and filtrate is cooled to 5 DEG C of crystallizes, insulated and stirred 2 hours, filters, 50 DEG C
It is vacuum dried to obtain 107g (0.288mol) trazodone, yield 89%.
Embodiment 1 present invention adds sodium hydroxide solution and prepares trazodone
Toward in 2L there-necked flask under room temperature, it is sequentially added into 100g (0.323mol) N-(the chloro-phenyl of 3-)-N '-(3-
Chloropropyl)-piperazine hydrochloride, 52.4g (0.388mol) pyridine triazolone, 1500mL isopropanol, starts
Mechanical agitation, adds 29.7g (0.743mol) sodium hydroxide, and nitrogen is protected, and is warming up to backflow, reaction
26 hours, HPLC detection N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine content was 0.02%.Control temperature
Degree is to 60～70 DEG C of heat filterings, and filtrate proceeds in reaction bulb, adds 120mL 10% sodium hydrate aqueous solution,
Stirring temperature rising reflux 8 hours, is cooled to 5 DEG C of crystallizes, insulated and stirred 2 hours, filters, and 50 DEG C of vacuum are done
Dry 110g (0.296mol) trazodone, yield 92%.
Embodiment 2 present invention adds potassium hydroxide solution and prepares trazodone
Toward in 2L there-necked flask under room temperature, it is sequentially added into 100g (0.323mol) N-(the chloro-phenyl of 3-)-N '-(3-
Chloropropyl)-piperazine hydrochloride, 52.4g (0.388mol) pyridine triazolone, 1500mL isopropanol, starts
Mechanical agitation, adds 29.7g (0.743mol) sodium hydroxide, and nitrogen is protected, and is warming up to backflow, reaction
26 hours, HPLC method detection N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine content was 0.02%.Control
Temperature proceeds in reaction bulb to 60～70 DEG C of heat filterings, filtrate, adds 120mL 10% potassium hydroxide aqueous solution,
Stirring temperature rising reflux 8 hours, is cooled to 5 DEG C of crystallizes, insulated and stirred 2 hours, filters, and 50 DEG C of vacuum are done
Dry 108g (0.290mol) trazodone, yield 90%.
Embodiment 3 uses trazodone synthetic hydrochloric acid trazodone prepared by the present invention
Toward in 500mL there-necked flask under room temperature, it is sequentially added into 50g (0.134mol) trazodone, 300mL
Ethanol, starts mechanical agitation, is warming up to 60 DEG C, after solid dissolves, drips 12mol/L HCl/water solution,
Regulation system pH is to 3, and then slow cooling is to 0 DEG C, separates out a large amount of white solid, insulated and stirred 2 hours,
Filtering, 50 DEG C are vacuum dried to obtain 51g (0.125mol) trazodone hydrochloride, yield 93%.
Detect impurity N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine in comparative example 1 and embodiment 1-3 respectively residual
Allowance.Detection method used and process be:
1.1 instrument and equipments, such as table 1 below.
Table 1
1.2 solution preparations
Standard solution (0.025 μ g/mL)
Diluent: acetonitrile, water and formic acid (100:900:1, v/v/v)
Sample solution
Sample solution (10mg/mL).
Diluent (acetonitrile, water and formic acid (100:900:1, v/v/v)).
1.2.1 MS/MS method parameter, such as table 2 below.
Table 2
Testing result such as table 3 below:
Table 3
From above testing result, the preparation method of the trazodone hydrochloride that the present invention provides, can accomplish by
The residual quantity control of critical impurities N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine of the generation in its preparation process
System within 2.5ppm, impurity N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl) in the most existing preparation technology-
The content of piperazine, therefore can directly meet the interior content to this impurity of industry and limit requirement.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all at this
Any amendment, equivalent and the improvement etc. made within bright spirit and principle, should be included in the present invention
Protection domain within.
Claims (10)
1. the preparation method of a trazodone hydrochloride, it is characterised in that comprise the following steps:
N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride is mixed in a solvent with pyridine triazolone,
Add alkali, temperature rising reflux；
Reaction system is carried out successively heat filtering, adds alkali liquor temperature rising reflux again；
Crystallize, it is thus achieved that trazodone；And
By gained trazodone and hydrochloric acid reaction.
2. preparation method as claimed in claim 1, it is characterised in that described pyridine triazolone is with described
The ratio of the amount of the material of N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride is 1～1.5:1.
3. preparation method as claimed in claim 1, it is characterised in that described alkali is sodium hydroxide, hydrogen-oxygen
Change the one in potassium, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine；Described
Alkali is 2～3:1 with the ratio of the amount of the material of described N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine hydrochloride.
4. preparation method as claimed in claim 1, it is characterised in that described solvent is n-butyl alcohol, isobutyl
Alcohol, normal propyl alcohol, isopropanol, ethanol, methanol, oxolane, 1,4-dioxane, N, N-dimethyl methyl
One in amide or DMAC N,N' dimethyl acetamide；Described solvent and described N-(the chloro-phenyl of 3-)-N '-(3-chlorine third
Base) the volume mass ratio of-piperazine hydrochloride is 10～30mL:1g.
5. preparation method as claimed in claim 1, it is characterised in that the temperature of described heat filtering is
50～75 DEG C.
6. preparation method as claimed in claim 1, it is characterised in that the concentration of described alkali liquor is
5%～20%wt；The solute of described alkali liquor is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, carbonic acid
One in hydrogen sodium, potassium bicarbonate, triethylamine, pyridine.
7. preparation method as claimed in claim 1, it is characterised in that described alkali liquor and the body of described solvent
Long-pending ratio is 1%～15%:1.
8. preparation method as claimed in claim 1, it is characterised in that the product of described temperature rising reflux includes
N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine, the terminal of described temperature rising reflux is that HPLC detects described
The content of N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine is less than 0.05%.
9. preparation method as claimed in claim 1, it is characterised in that the temperature of described crystallize is
-5～15 DEG C, the time is 1～4 hour.
10. impurity N-(the chloro-phenyl of 3-)-N '-(3-chloropropyl)-piperazine in a trazodone hydrochloride preparation
Content reduces method, it is characterised in that use the preparation method described in claim 1～9 to react.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610188125.0A CN105777745A (en) | 2016-03-29 | 2016-03-29 | Preparation method of trazodone hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610188125.0A CN105777745A (en) | 2016-03-29 | 2016-03-29 | Preparation method of trazodone hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105777745A true CN105777745A (en) | 2016-07-20 |
Family
ID=56391221
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610188125.0A Pending CN105777745A (en) | 2016-03-29 | 2016-03-29 | Preparation method of trazodone hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105777745A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019154770A1 (en) | 2018-02-07 | 2019-08-15 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Continuous process for the preparation of trazodone |
| CN117517545A (en) * | 2023-12-08 | 2024-02-06 | 重庆锐恩医药有限公司 | Method for detecting trazodone hydrochloride related substances |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101772490A (en) * | 2007-08-03 | 2010-07-07 | 方济各安吉利克化学联合股份有限公司 | Trazodone and trazodone hydrochloride in purified form |
-
2016
- 2016-03-29 CN CN201610188125.0A patent/CN105777745A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101772490A (en) * | 2007-08-03 | 2010-07-07 | 方济各安吉利克化学联合股份有限公司 | Trazodone and trazodone hydrochloride in purified form |
Non-Patent Citations (2)
| Title |
|---|
| 盐酸曲唑酮的合成;薛叙明等;《中国医药工业杂志》;20081231;第39卷(第11期);第808-810页 * |
| 盐酸曲唑酮的合成;陈国良等;《中国药物化学杂志》;20020430;第12卷(第2期);第92-93页 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019154770A1 (en) | 2018-02-07 | 2019-08-15 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Continuous process for the preparation of trazodone |
| CN111886235A (en) * | 2018-02-07 | 2020-11-03 | 方济各安吉利克化学联合股份有限公司 | Continuous process for the preparation of trazodone |
| KR20200130249A (en) * | 2018-02-07 | 2020-11-18 | 아지엔드 키미쉐 리유나이트 안젤리니 프란체스코 에이.씨.알.에이.에프. 에스.피.에이 | Continuous process for the production of trazodone |
| JP2021512888A (en) * | 2018-02-07 | 2021-05-20 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニＡｚｉｅｎｄｅ Ｃｈｉｍｉｃｈｅ Ｒｉｕｎｉｔｅ Ａｎｇｅｌｉｎｉ Ｆｒａｎｃｅｓｃｏ Ａ．Ｃ．Ｒ．Ａ．Ｆ．Ｓｏｃｉｅｔａ Ｐｅｒ Ａｚｉｏｎｉ | Continuous process for the preparation of trazodone |
| AU2019217490B2 (en) * | 2018-02-07 | 2023-06-29 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Continuous process for the preparation of trazodone |
| CN111886235B (en) * | 2018-02-07 | 2023-06-30 | 方济各安吉利克化学联合股份有限公司 | Continuous process for preparing trazodone |
| JP7301858B2 (en) | 2018-02-07 | 2023-07-03 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | Continuous process for the preparation of trazodone |
| KR102646651B1 (en) | 2018-02-07 | 2024-03-13 | 안젤리니 에스.피.에이. | Continuous process for the preparation of trazodone |
| US12221438B2 (en) | 2018-02-07 | 2025-02-11 | Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. | Continuous process for the preparation of trazodone |
| CN117517545A (en) * | 2023-12-08 | 2024-02-06 | 重庆锐恩医药有限公司 | Method for detecting trazodone hydrochloride related substances |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105017260B (en) | Preparation method of sitagliptin intermediate triazolopyrazine derivative | |
| CN107915738B (en) | For synthesizing Ba Rui for the preparation method of the key intermediate 2 of Buddhist nun | |
| CN105712984A (en) | Preparation method of Azilsartan | |
| CN101357911B (en) | Method for synthesizing (z)-2-(alpha-methoxyimino)furan-ammonium acetate | |
| KR102646651B1 (en) | Continuous process for the preparation of trazodone | |
| CN105777745A (en) | Preparation method of trazodone hydrochloride | |
| CN107235959A (en) | A kind of novel method for synthesizing for preparing cancer therapy drug Niraparib | |
| CN103965125A (en) | Synthetic method of 3,3'-binitro-5,5'-di-1,2,4-triazole | |
| CN108530364B (en) | Crystal form of 3- (4-methyl-1H-imidazole-1-yl) -5-trifluoromethyl aniline monohydrochloride and application thereof | |
| CN102924311A (en) | L-ornithine-L-aspartate preparation method | |
| CN101362729B (en) | Valsartan postprocessing method | |
| CN108276414B (en) | A kind of preparation method of citric acid tropsch imatinib | |
| CN106957299A (en) | A kind of lenalidomide preparation method | |
| CN103086998B (en) | Synthetic method of 3-amino-4-hydroxyfurazan | |
| CN109535083A (en) | The preparation method of 2,4,5-triamino-6-hydroxypyrimidine sulfate and folic acid | |
| CN108250091A (en) | A kind of preparation method of alprazolam intermediate | |
| CN108864041A (en) | A kind of preparation method of medicine intermediate tetrazole compound | |
| CN104262260B (en) | The preparation method of high purity olmesartan medoxomill intermediate 2-propyl imidazole-4,5-dicarboxylic acid and application | |
| CN114685401A (en) | Synthesis method of di (4-methylpiperazine-1-yl) ketone | |
| CN105646472A (en) | Preparation method of arotinolol hydrochloride | |
| WO2016116074A1 (en) | A method of producing highly pure rilpivirine and its salts | |
| CN112457304A (en) | Preparation method of nifuratel | |
| CN105601545B (en) | A kind of synthetic method of sulphoamidine | |
| CN115521255B (en) | Hydroxychloroquine solvate and preparation method and application thereof | |
| CN104151299B (en) | Compound, crystal-form compound and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160720 |
|
| RJ01 | Rejection of invention patent application after publication |