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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Abstract
The invention belongs to the technical field of medicine synthesis, and discloses a synthetic method of olanzapine related substances compound I and compound II, which 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. The preparation method provided by the invention has the advantages of short reaction route, mild condition, low overall cost and high yield and purity, and provides reliable substance guarantee for subsequent quality control research and safety property research in the olanzapine preparation process.
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.
Claims (10)
1. The synthetic method of the olanzapine related substance compound I and the compound II is characterized in that the synthetic route comprises the following steps:
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 a compound I in an organic solvent, adding an inorganic alkali solution at 0 ℃, then adding acetyl chloride, continuously stirring and reacting at 0 ℃ until the compound I disappears, separating and extracting, and purifying by silica gel column chromatography to obtain a compound II;
the chemical formulas of the compound I and the compound II are as follows:
2. a process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S1, the organic solvent is one or more of methanol, ethanol, dichloromethane, chloroform, N-dimethylformamide, and N-methylpyrrolidone.
3. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S1, the molar ratio of olanzapine to Oxone to sodium hydroxide is 1: 1-2: 2-4.
4. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S1, the olanzapine, the Oxone and the sodium hydroxide are added in a ratio of 5-10 mL of organic solvent and 10-15 mL of water to 1g of olanzapine.
5. The method for synthesizing olanzapine related substances compound I and compound II according to claim 1, wherein the reaction temperature is controlled to be 10-80 ℃ in the step S1.
6. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 5, characterized in that: in the step S1, the reaction temperature is controlled to be 20-25 ℃.
7. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S2, the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane or toluene.
8. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S2, the compound I and the organic solvent are added in a proportion that every 1g of the compound I is dissolved in 10-15 mL of the organic solvent.
9. The process for the synthesis of olanzapine related substances compound I and compound II according to claim 1, characterized in that: in the step S2, the concentration of the used inorganic alkali liquor is 10-40%.
10. The method for synthesizing olanzapine related substances compound I and compound II according to claim 1, wherein the molar ratio of the compound I, the inorganic base and the acetyl chloride is 1: 1-3.
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