CN111484460B - Synthetic method of olanzapine related substance compound I and compound II - Google Patents
Synthetic method of olanzapine related substance compound I and compound II Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 63
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 title claims abstract description 52
- 229960005017 olanzapine Drugs 0.000 title claims abstract description 51
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 239000000126 substance Substances 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000003960 organic solvent Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 12
- 238000000605 extraction Methods 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract 4
- 238000001953 recrystallisation Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims 2
- 238000011097 chromatography purification Methods 0.000 claims 1
- 229910001882 dioxygen Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 10
- 238000011160 research Methods 0.000 abstract description 7
- 238000010898 silica gel chromatography Methods 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000007788 liquid Substances 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 238000000926 separation method Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 230000008034 disappearance Effects 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000001514 detection method Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 108010009685 Cholinergic Receptors Proteins 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000034337 acetylcholine receptors Human genes 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010525 oxidative degradation reaction Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/12—1,5-Benzodiazepines; Hydrogenated 1,5-benzodiazepines
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明属于药物合成技术领域，公开了一种奥氮平有关物质化合物I和化合物II的合成方法，包括如下步骤：S1、化合物I的合成：将奥氮平、有机溶剂和水加入反应瓶中，依次加入Oxone和氢氧化钠，持续反应，直至奥氮平斑点消失，而后将体系的pH调至6～7，经萃取和重结晶后，得到化合物I；S2：化合物II的合成：将化合物I溶于有机溶剂中，在0℃下加入无机碱液，随后加入乙酰氯，继续在0℃下搅拌反应，直至化合物I消失，分液萃取，经硅胶柱层析纯化，得到化合物II。本发明提供的制备方法具有反应路线简短、条件温和、整体成本低、产率和纯度高的优点，为奥氮平制备过程中的后续质量控制研究及安全性质研究提供了可靠的物质保证。The invention belongs to the technical field of drug synthesis, and discloses a method for synthesizing olanzapine related substances, compound I and compound II, comprising the following steps: S1. Synthesis of compound I: adding olanzapine, an organic solvent and water into a reaction flask , Oxone and sodium hydroxide were added in turn, and the reaction was continued until the olanzapine spots disappeared, and then the pH of the system was adjusted to 6 to 7. After extraction and recrystallization, compound I was obtained; S2: Synthesis of compound II: the compound I was dissolved in an organic solvent, inorganic lye was added at 0°C, followed by addition of acetyl chloride, and the reaction was continued to be stirred at 0°C until compound I disappeared, and then extracted by liquid separation and purified by silica gel column chromatography to obtain compound II. The preparation method provided by the invention has the advantages of short reaction route, mild conditions, low overall cost, high yield and high purity, and provides a reliable material guarantee for the follow-up quality control research and safety property research in the preparation process of olanzapine.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthetic method of olanzapine related substance compound I and compound II.
Background
Olanzapine (sold under the trade name of replanole) is a mental drug developed and marketed by American etiquette, and has the chemical name of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b ] [1,5] benzodiazepine, and the structural formula is shown as follows (the structural formula is deleted). The medicine is a novel atypical neuroleptic, can combine with dopamine receptor, 5-HT receptor and cholinergic receptor and exert antagonistic action, and is mainly used for treating schizophrenia.
In order to study and control the quality of olanzapine, related substances thereof need to be prepared as a reference substance. The Journal of Pharmaceutical & Biomedical Analysis,2011,56(2):413-418 of the document reports a group of olanzapine oxidative degradation products, the structures of which are shown in I and II. The authors of this document speculate about the possible mechanism of the degradation process, but do not provide a process for the preparation of compounds I and II, nor do other documents and patents report the synthesis of compounds I and II.
The quality and safety of the medicine are directly affected by the type and content of related substances in the medicine, strict quality control is required to be performed in the production of the medicine according to related regulations of national medicine management, and related safety research and quality control are required in the production of new medicine impurities found in the production. Therefore, the research on the preparation method and safety of related substances of marketed drugs is of great significance, and the development of the preparation method of related substances is the basis of further safety research.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthetic method of olanzapine related substances, namely a compound I and a compound II.
In order to solve the problems, the technical scheme of the invention is as follows:
the method comprises the following steps:
s1, Synthesis of Compound I: adding olanzapine, an organic solvent and water into a reaction bottle, sequentially adding Oxone and sodium hydroxide, continuously reacting until olanzapine spots disappear, adjusting the pH of the system to 6-7, and extracting and recrystallizing to obtain a compound I;
s2: synthesis of Compound II: dissolving the compound I in an organic solvent, adding an inorganic alkali solution at 0 ℃, then adding acetyl chloride, continuing stirring and reacting at 0 ℃ until the compound I disappears, separating and extracting, and purifying by silica gel column chromatography to obtain the compound II.
Preferably, in step S1, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, N-dimethylformamide and N-methylpyrrolidone.
The organic solvent is most preferably N, N-dimethylformamide.
Preferably, in the step S1, the molar ratio of olanzapine to Oxone to sodium hydroxide is 1: 1-2: 2-4.
More preferable molar ratio of olanzapine, Oxone and sodium hydroxide is 1: 1-1.2: 3-4.
More preferably, in step S1, the olanzapine, Oxone and sodium hydroxide are added in a ratio of 5 to 10mL of organic solvent and 10 to 15mL of water per 1g of olanzapine.
Preferably, in the step S1, the reaction temperature is controlled to be 10 to 80 ℃.
More preferably, in the step S1, the reaction temperature is controlled to be 20 to 25 ℃.
Preferably, in step S2, the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane and toluene.
The organic solvent is most preferably toluene.
Preferably, in step S2, the compound I and the organic solvent are added in a ratio of dissolving in 10 to 15mL of organic solvent per 1g of compound I.
Preferably, in the step S2, the concentration of the inorganic alkali solution used is 10% to 40%.
The concentration of the inorganic alkali liquor is most preferably 10-15%.
Preferably, the molar ratio of the compound I, the inorganic base and the acetyl chloride is 1: 1-3.
A more preferable molar ratio of the compound I, the inorganic base and the acetyl chloride is 1:1 to 1.1.
The invention has the beneficial effects that: the invention provides a preparation method of a group of olanzapine related substance compounds I and II for the first time, the method uses cheap and easily available raw materials and has a short route, the synthesis of two target compounds can be realized through two-step reaction, and the method also has the advantages of high total yield and high purity of final products; the preparation method provided by the invention provides reliable substance guarantee for subsequent quality control research and safety property research in the olanzapine preparation process, and has obvious technical and economic benefits.
Detailed Description
The principles and features of this invention are described below in conjunction with examples which are set forth to illustrate, but are not to be construed to limit the scope of the invention.
The synthetic method of the olanzapine related substance compound I and the compound II adopts the following synthetic route:
the synthesis method comprises the following steps:
s1, Synthesis of Compound I: adding olanzapine, an organic solvent and water into a reaction bottle, sequentially adding Oxone and sodium hydroxide, continuously reacting until olanzapine spots disappear, adjusting the pH of the system to 6-7, and extracting and recrystallizing to obtain a compound I;
s2: synthesis of Compound II: dissolving the compound I in an organic solvent, adding an inorganic alkali solution at 0 ℃, then adding acetyl chloride, continuing stirring and reacting at 0 ℃ until the compound I disappears, separating and extracting, and purifying by silica gel column chromatography to obtain the compound II.
In some preferred embodiments, in step S1, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, N-dimethylformamide and N-methylpyrrolidone. Most preferred is N, N-dimethylformamide.
In some preferred embodiments, the molar ratio of olanzapine, Oxone and sodium hydroxide in step S1 is 1:1 to 2:2 to 4. More preferable molar ratio of olanzapine, Oxone and sodium hydroxide is 1: 1-1.2: 3-4.
Most preferably, in step S1, olanzapine, Oxone and sodium hydroxide are added in a ratio of 5-10 mL of organic solvent and 10-15 mL of water per 1g of olanzapine.
Proved by experiments of an inventor, olanzapine, Oxone and sodium hydroxide are in a molar ratio of 1: 1-2: 2-4, so that complete reaction can be effectively ensured, and no olanzapine is left in a reaction product.
Through further experiments, the reaction effect can be achieved when the molar ratio of olanzapine to Oxone to sodium hydroxide is in the range of 1: 1-2: 2-4 to 1: 1-1.2: 3-4, and the raw materials can be saved by adopting the molar ratio of 1: 1-1.2: 3-4.
Through experimental study of the inventor, when the addition ratio of olanzapine, Oxone and sodium hydroxide is 5-10 mL of organic solvent and 10-15 mL of water added to 1g of olanzapine, the raw material consumption is saved most on the premise of ensuring complete reaction.
In some preferred embodiments, in the step S1, the reaction temperature is controlled to be 10-80 ℃. The reaction temperature is most preferably controlled to be 20-25 ℃.
The inventor determines through experiments that the reaction of step S1 can be completed within a reasonable time at a reaction temperature of 10-80 ℃ for 1-5 hours. And the reaction temperature of 20-25 ℃ is adopted, so that the yield is highest.
In some preferred embodiments, in step S2, the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane or toluene, and most preferably toluene.
In some preferred embodiments, in step S2, the compound I and the organic solvent are added in a ratio of dissolving in 10 to 15mL of the organic solvent per 1g of the compound I.
In some preferred embodiments, in the step S2, the concentration of the inorganic alkali solution used is 10% to 40%. The most preferable concentration of the inorganic alkali liquor is 10-15%.
In some preferred embodiments, the molar ratio of compound I, inorganic base and acetyl chloride is 1:1 to 3. The most preferable molar ratio of the compound I, the inorganic base and the acetyl chloride is 1: 1-1.1.
The above-mentioned addition ratio is selected in the same manner as in step S1.
The progress of the reaction in steps S1 and S2 can be monitored by conventional detection methods in the art (e.g., TLC, HPLC, or NMR), and is generally at the end of the reaction when olanzapine and compound I disappear. The present invention preferably employs TLC detection to monitor the progress of the reaction.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1:
example 1 of the present invention provides a preparation method of compound I, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
olanzapine (8.0g, 25.6mmol), N-dimethylformamide (40mL) and water (80mL) were added to a reaction flask and Oxone (7.9g, 25.6mmol) was added with stirring and after the addition was completed stirring was continued at 25 ℃ for 2h followed by sodium hydroxide solid (3.1g, 76.8mmol) and stirring was continued at 25 ℃ for 1h and disappearance of starting material was detected by TLC. The pH of the reaction mixture was adjusted to 6 to 7 using 2M hydrochloric acid, methylene chloride (120mL) was added to the reaction mixture, followed by liquid separation and extraction, and the organic layer was washed with water (50 mL. times.3) and saturated brine (50 mL. times.3) in this order. And drying the organic layer by using anhydrous sodium sulfate, performing suction filtration, evaporating the filtrate under reduced pressure, and recrystallizing the crude product by using acetonitrile (55mL) to obtain a pure product of the compound I.
The method is adopted to prepare 6.7g of light yellow solid, the yield is 86.5 percent, and the purity is 99.1 percent.
The compound I prepared in this example was identified with the following results:
ESI-MS(m/z):303.1；
1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.45(s,1H),7.36(dd,J＝7.4,1.5Hz,1H),7.24(td,J＝7.5,1.5Hz,1H),7.01(td,J＝7.5,1.5Hz,1H),6.90(dd,J＝7.5,1.4Hz,1H),6.15(s,1H),3.56(t,J＝5.1Hz,4H),2.27(t,J＝5.2Hz,4H),2.19(s,3H)。
13C NMR(101MHz,DMSO-d6)δ191.60,155.49,153.85,139.91,137.88,124.76,123.38,121.35,118.48,109.05,53.57,47.61,45.98。
example 2:
example 2 of the present invention provides a method for preparing compound I:
olanzapine (6.0g, 19.2mmol), N-methylpyrrolidone (30mL) and water (60mL) were added to a reaction flask and added with stirring
(5.9g, 19.2mmol) and after addition stirring was continued at 25 ℃ for 2h, followed by addition of sodium hydroxide solid (2.3g, 57.6mmol) and continued stirring at 25 ℃ for 1h, TLC detection of disappearance of starting material. The pH of the reaction mixture was adjusted to 6 to 7 using 2M hydrochloric acid, methylene chloride (90mL) was added to the reaction mixture, followed by liquid separation and extraction, and the organic layer was washed with water (40 mL. times.3) and saturated brine (40 mL. times.3) in this order. The organic layer was dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to remove the filtrate, and the crude product was recrystallized from acetonitrile (41mL) to give pure compound I.
The method is adopted to prepare 4.6g of light yellow solid, the yield is 79.2%, and the purity is 98.9%.
Example 3:
example 3 of the present invention provides a process for the preparation of compound I:
olanzapine (4.0g, 12.8mmol), N-dimethylformamide (20mL) and water (40mL) were added to the reaction flask with stirring
(4.0g, 12.8mmol) and after addition stirring was continued for 1.5h at 40 ℃ followed by addition of sodium hydroxide solid (1.5g, 38.4mmol) and continued stirring for 0.5h at 40 ℃ with disappearance of starting material by TLC. The system pH was adjusted to 6 to 7 using 2M hydrochloric acid, methylene chloride (60mL) was added to the reaction mixture, followed by liquid separation and extraction, and the organic layer was washed with water (25 mL. times.3) and saturated brine (25 mL. times.3) in this order. And drying the organic layer by using anhydrous sodium sulfate, performing suction filtration, performing reduced pressure evaporation to remove the filtrate, and recrystallizing the crude product by using acetonitrile (20mL) to obtain a pure product of the compound I.
The method is adopted to prepare 2.9g of light yellow solid, the yield is 74.9 percent, and the purity is 98.6 percent.
Example 4:
example 4 of the present invention provides a preparation method of compound II, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
compound I (5.0g, 16.5mmol) was dissolved in toluene (60mL), 10% by mass aqueous sodium carbonate (20mL) was added at 0 deg.C, followed by acetyl chloride (1.3mL,18.2mmol), the reaction was continued at 0 deg.C for 2h, disappearance of compound I was detected by TLC, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (40mL), the organic layers were combined and washed with water (25 mL. times.3) and saturated brine (25 mL. times.3). The organic layer was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate ═ 2:1, v/v) to give a pure compound II.
The white solid obtained by the method is 5.5g, the yield is 96.6 percent, and the purity is 99.0 percent.
The compound II prepared in this example was identified with the following results:
ESI-MS(m/z):345.3；
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.30(dd,J＝7.4,1.5Hz,1H),7.29(td,J＝7.5,1.5Hz,1H),7.05(td,J＝7.5,1.5Hz,1H),6.94(dd,J＝7.5,1.4Hz,1H),6.18(s,1H),3.55(t,J＝5.1Hz,4H),2.28(t,J＝5.2Hz,4H),2.19(s,3H),2.12(s,3H)。
13C NMR(101MHz,DMSO-d6)δ187.51,167.43,155.85,149.67,138.96,138.54,128.76,124.45,121.09,118.97,116.74,55.38,48.72,45.55,21.03。
example 5:
example 5 of the present invention provides a method of preparing compound II:
compound I (5.5g, 18.2mmol) was dissolved in toluene (70mL), 10% by mass aqueous cesium carbonate (65mL) was added at 0 deg.C, followed by acetyl chloride (1.4mL,20.0mmol), the reaction was continued at 0 deg.C for 2h, disappearance of compound I was detected by TLC, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (45mL), the organic layers were combined and washed with water (25 mL. times.3) and saturated brine (25 mL. times.3). The organic layer was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate ═ 2:1, v/v) to give a pure compound II.
The white solid obtained by the method is 5.4g, the yield is 86.2 percent, and the purity is 98.7 percent.
Example 6:
example 6 of the present invention provides a method for preparing compound II:
compound I (4.0g, 13.2mmol) was dissolved in tetrahydrofuran (40mL), and 10% by mass aqueous sodium carbonate (16mL) was added at 0 deg.C followed by acetyl chloride (1.0mL,14.6mmol), the reaction was continued at 0 deg.C for 2h, disappearance of compound I was detected by TLC, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (35mL), the organic layers were combined and washed with water (20 mL. times.3) and saturated brine (20 mL. times.3). The organic layer was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was evaporated under reduced pressure, and the crude product was purified by silica gel column chromatography (mobile phase: petroleum ether/ethyl acetate ═ 2:1, v/v) to give a pure compound II.
The white solid obtained by the method is 4.2g, the yield is 92.2 percent, and the purity is 98.8 percent.
From the results of the above examples, it is understood that the synthesis method of the present invention can achieve a synthesis yield of the compound I related to olanzapine of 72% or more and a purity of 98% or more; the synthesis yield of the compound II can reach more than 85 percent, and the purity can be controlled to be more than 98 percent. Has the advantages of high yield and high purity of final products.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
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