CN111362816B - Preparation method of tamoxifen related substance - Google Patents
Preparation method of tamoxifen related substance Download PDFInfo
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Abstract
The invention provides a preparation method of tamoxifen related substances shown as a formula (1), which comprises the following steps: the method comprises the following steps: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol shown in a formula (4) under an acidic condition to obtain a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5); step two: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5) with a compound 4- [2- (dimethylamino) ethoxy ] benzophenone shown in a formula (6) to obtain a compound shown in a formula (7); step three: reacting the compound shown in the formula (7) under an acidic condition to obtain a crude product shown in the formula (1). The synthesis process has reasonable design and strong operability, and the reagents used in the preparation process are simple and easy to obtain.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of tamoxifen related substances.
Background
Tamoxifen (Tamoxifen) has a chemical name of (Z) -2- [4- (1, 2-diphenyl-1-butene) phenoxy ] -N, N-dimethylethylamine, is a triphenylene compound, is an antiestrogen drug developed by taking diethylstilbestrol estrogen as a precursor, forms a stable compound with an estrogen receptor, and is transported into a nucleus to prevent the opening of a chromosome gene, so that the growth and development of cancer cells are inhibited, and the Tamoxifen has a good effect on the aspect of treating late-stage breast cancer and ovarian cancer, and has a structure shown as a formula I:
tamoxifen was developed by Imperial chemical Industry (ICH) and was first used clinically in 1971 and was approved by the U.S. FDA in 1978 for the treatment of perimenopausal and postmenopausal breast cancers. Although tamoxifen has a good curative effect on treating advanced breast cancer and ovarian cancer, serious adverse reactions still occur, and the adverse reactions are related to the pharmacological activity of tamoxifen and related substances in tamoxifen, so that the research on related substances is carried out in a normative way, the adverse reactions are controlled within a safe and reasonable limit range, and the adverse reactions are directly related to the quality and safety of tamoxifen, therefore, the method has great significance for synthesizing the related substances of tamoxifen, can be used for qualitative and quantitative analysis of the related substances in tamoxifen production, can improve the quality standard of tamoxifen, and has important guiding significance for safe medication of the masses
The structure of the tamoxifen related substance to be prepared by the invention is shown as the formula (1):
the tamoxifen is an important impurity in pharmacopoeia, and the synthesis routes of tamoxifen are reported on the market at present, but the synthesis methods of specific related substances of tamoxifen are few.
In addition, because the related substance of the tamoxifen to be prepared by the invention is one of all impurities with the most complex structure, is generated in the process of synthesizing the tamoxifen body, has the structure closest to that of the tamoxifen body, and the related substance obtained according to the conventional tamoxifen synthesis route has less content and cannot be obtained by separation, the invention provides a new synthesis process which is reasonable in design and can obtain a high-purity yield substance.
Disclosure of Invention
The invention aims to provide a tamoxifen related substance and a preparation method thereof.
The technical scheme of the invention is as follows:
a tamoxifen related substance has a structure shown in formula (1):
the preparation method of the tamoxifen related substance shown as the formula (1) comprises the following preparation route:
the preparation method comprises the following steps:
the method comprises the following steps: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol shown in a formula (4) under an acidic condition to obtain a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5);
step two: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5) with a compound 4- [2- (dimethylamino) ethoxy ] benzophenone shown in a formula (6) to obtain a compound shown in a formula (7);
step three: reacting a compound shown in a formula (7) under an acidic condition to obtain a crude product shown in a formula (1);
step four: and (3) purifying the crude tamoxifen related substance shown in the formula (1) to obtain a pure tamoxifen related substance shown in the formula (1).
Preferably, the first and second electrodes are formed of a metal,
the preparation method specifically comprises the following steps:
the method comprises the following steps: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol shown in a formula (4) under an acidic condition at 30-60 ℃ for 7-13 hours to obtain a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5);
step two: reacting 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in the formula (5) with 4- [2- (dimethylamino) ethoxy ] benzophenone shown in the formula (6) at the temperature of minus 30-78 ℃ for 4-12 hours by taking an aprotic solvent as a reaction solvent to obtain a compound shown in the formula (7); the molar ratio of the compound shown in the formula (5) to the compound shown in the formula (6) is 1: 1;
step three: reacting the compound shown in the formula (7) for 5-13 hours at the temperature of 30-90 ℃ under an acidic condition to obtain a crude product shown in the formula (1);
step four: and (2) carrying out preparation separation on the crude tamoxifen related substances in the formula (1) by high performance liquid chromatography, concentrating after preparation, adding an alkaline water solution with the concentration of 7-10% to adjust the pH to 8-11, then adding an organic solvent to the crude tamoxifen related substances to carry out extraction, drying and concentration, recrystallizing the obtained product, and finally obtaining the pure tamoxifen related substances in the formula (1).
It is further preferred that the first and second liquid crystal compositions,
in the first step, the acid is protonic acid, and is selected from one of hydrochloric acid, phosphoric acid and sulfuric acid, or a mixture of the two or more;
in the second step, the aprotic solvent is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF and DMSO;
in the third step, the acid is selected from formic acid, acetic acid or a mixture of the two.
In the fourth step, the used alkali is inorganic alkali, and is selected from one of sodium hydroxide, potassium hydroxide and sodium bicarbonate; the organic solvent is selected from one of ethyl acetate, dichloromethane and chloroform.
It is further preferred that the first and second liquid crystal compositions,
in the first step, the acid is hydrochloric acid or sulfuric acid;
in the second step, the aprotic solvent is acetone, acetonitrile, tetrahydrofuran or a mixture of two or more of the acetone, the acetonitrile and the tetrahydrofuran;
in the third step, the acid is formic acid.
It is further preferred that the first and second liquid crystal compositions,
in the first step, the reaction temperature is preferably 45 ℃, and the reaction time is preferably 10 hours;
in the second step, the reaction temperature is preferably-68 ℃, and the reaction time is preferably 9 h;
in the third step, the reaction temperature is preferably 80 ℃, and the reaction time is preferably 9 h.
In the fourth step, the pH is preferably adjusted to 8.5-9.5. More preferably, the pH is adjusted to 9.
In the invention, the synthesis method of the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4) is as follows:
dissolving the compound 2- (4-bromophenoxy) -N, N-dimethylethylamine of the formula (3) and the compound 2- (4-bromophenyl) -1-phenylbutanone of the formula (2) in an aprotic solvent for reaction to obtain the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4).
Preferably, the first and second electrodes are formed of a metal,
the synthesis method of the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4) is as follows:
dissolving a compound 2- (4-bromophenoxy) -N, N-dimethylethylamine of a formula (3) and a compound 2- (4-bromophenyl) -1-phenylbutanone of a formula (2) in an aprotic solvent, cooling to minus 30-78 ℃, then dropwise adding an N-butyllithium solution, reacting for 5-12 hours after the addition is finished, adding water and dichloromethane after the reaction is completed, extracting, drying, concentrating to dryness, and recrystallizing the concentrate to obtain the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4);
the molar ratio of the compound shown in the formula (3) to the compound shown in the formula (2) is 1: 1.
further preferably, in the preparation of the compound of formula (4),
the aprotic solvent used is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF and DMSO.
More preferably, the aprotic solvent is selected from one or more of acetone, chloroform, tetrahydrofuran, and acetonitrile.
The polarity of the solvent used for recrystallization was petroleum ether V: and (3) ethyl acetate V is 3-5: 1. Preferred are petroleum ethers V: ethyl acetate V ═ 4: 1.
The reaction temperature is preferably-58 ℃ and the reaction time is preferably 8 hours.
The invention has the following technical effects:
the invention provides a preparation method of tamoxifen related substances, the synthesis process of the invention has reasonable design and strong operability, the reagents used in the preparation process are simple and easy to obtain, and the obtained products are verified and characterized by means of infrared, mass spectrum, nuclear magnetism and the like through practical experiments.
Drawings
FIG. 1 is a mass spectrum of an infrared absorption spectrum of a compound represented by the formula (1) in example 2.
FIG. 2 shows a nuclear magnetic resonance hydrogen spectrum of a compound represented by the formula (1) in example 2.
FIG. 3 is a nuclear magnetic resonance carbon spectrum of the compound represented by the formula (1) in example 2.
FIG. 4 is a mass spectrum of the compound represented by the formula (1) in example 2.
Detailed Description
The starting material of the present invention, compound 2- (4-bromophenoxy) -N, N-dimethylethylamine represented by formula (3), is commercially available.
A preparation method of a compound 2- (4-bromophenyl) -1-phenylbutanone shown as a formula (2) comprises the following steps:
1) adding a bromobenzene compound a (158g) and phenylacetyl chloride compound b (120g) into dichloromethane (700mL), and cooling to 0-5 ℃; then anhydrous aluminum trichloride (134g) was added in portions; and reacting for 2 hours at low temperature after the addition is finished.
2) After naturally warming to room temperature, the reaction mixture was allowed to react overnight, and the reaction mixture was poured into ice water (800mL) to separate layers.
3) The organic phase was extracted 2 times with water (400mL), then washed with saturated brine, combined, dried and spun dry. Column chromatography (PE: EA 50: 1) gave a white solid, the compound represented by formula (2) (44 g).
Example 1 preparation of 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol Compound represented by formula (4)
Dissolving 2- (4-bromophenoxy) -N, N-dimethylethylamine (8.30g, 34.20mmol) as a compound represented by the formula (3) and 2- (4-bromophenyl) -1-phenylbutanone (10.0g, 33.10mmol) as a compound represented by the formula (2) in 350ml of tetrahydrofuran, cooling to-58 ℃, then dropwise adding an N-butyllithium solution (2.50mol/L, 14.5ml), slowly raising the temperature to room temperature after the dropwise adding is finished, reacting for 8 hours, extracting, drying and concentrating to dryness after the reaction is finished, and concentrating the concentrate by using petroleum ether: ethyl acetate 4:1 to yield 13.75g of 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol as a compound in 88.9% yield.
Example 2 preparation of tamoxifen related substances represented by formula (1)
The method comprises the following specific steps:
the method comprises the following steps: preparation of a Compound represented by the formula (5): 35ml of a 6mol/L aqueous hydrochloric acid solution was added to a compound of the formula (4), 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol (7.50g,16.10mmol), and the mixture was reacted at 45 ℃ for 10 hours, followed by completion of the reaction of the starting materials, concentration under reduced pressure to dryness, addition of 100ml of water and 100ml of dichloromethane, adjustment of pH to 9.0 with an 8% sodium hydroxide solution, extraction, drying, and concentration to dryness to obtain 6.83g of the compound of the formula (5), 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene, as an oil, in a yield of 94.7%.
Step two: preparation of a Compound represented by the formula (7): dissolving 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene (6.50g, 14.47mmol) of a compound of formula (5) and 4- [2- (dimethylamino) ethoxy ] benzophenone (3.90g,14.49mmol) of a compound of formula (6) in 150ml of tetrahydrofuran, cooling to-68 ℃, slowly adding an n-butyllithium solution (2.50mol/L, 7ml) dropwise thereto, continuing the reaction for 9 hours after the dropwise addition is finished, then adding 100ml of saturated saline, extracting an aqueous phase with 100ml of ethyl acetate, combining organic phases, drying and concentrating to dryness to obtain 10.0g of a crude product, and preparing and purifying the crude product by using a High Performance Liquid Chromatography (HPLC), wherein the formula is as follows:
a chromatographic column: gray ID50nm x 450 preparative columns
Mobile phase:
| Time | water (0.1% trifluoroacetic acid) | |
| 0 | 70 | 30 |
| 20 | 60 | 40 |
| 30 | 60 | 40 |
Flow rate: 65mL/min
Detection wavelength: 254nm
Sample introduction volume: 5.0mL (400mg/1mL acetonitrile), after preparation, acetonitrile is concentrated at 45 ℃, PH 9 is adjusted with 8% sodium hydroxide solution, 100mL dichloromethane is added for extraction and separation, the aqueous phase is extracted once with 70mL ethyl acetate, the organic phases are combined, dried and concentrated to dryness to obtain 6.72g of the compound of formula (7), yield: 72.6 percent.
Step three: preparation of tamoxifen related substance shown in formula (1)
Formic acid was added to the compound of formula (7) (5.0g,7.80mmol) and reacted at 80 ℃ for 9 hours, the reaction of the starting materials was checked to be complete, the solvent was concentrated, 100ml of water and 150ml of dichloromethane were added to extract, dried and concentrated to dryness to give 4.50g of the crude compound of formula (1).
Step four: the compound of formula (1) obtained in the above step is subjected to preparative isolation under the following conditions:
a chromatographic column: gray ID50nm x 450 preparative columns
Mobile phase:
| Time | water (0.1% trifluoroacetic acid) | |
| 0 | 30 | 70 |
| 15 | 30 | 70 |
| 18 | 20 | 80 |
| 24 | 20 | 80 |
| 25 | 30 | 70 |
| 30 | 30 | 70 |
Flow rate: 60mL/min
Detection wavelength: 254nm
Sample introduction volume: 5.0mL (30mg/1mL acetonitrile)
After the preparation, the mixture is concentrated under reduced pressure at 45 ℃, 8% NaOH solution is added to adjust the pH to 9.0, 200ml of dichloromethane is added for extraction, drying and concentration are carried out till dryness, and the obtained product is extracted by isopropanol: water 2: 1, and finally obtaining 3.12g of a pure product of the formula (1) in yield: and (3.9).
The structure of the tamoxifen related substances is confirmed.
Mass Spectrometry (solvent: methanol, ESI (+)).
MS(ESI):625.4[M+H]+
Nuclear magnetic hydrogen spectrum data
From the chemical shift values, the coupling constant values and the various two-dimensional spectra:
the delta 0.89/0.92(3H, t) and 2.45/2.50(2H, m) are hydrogen on the ethyl branch chain by 1HNMR, H-H COSY and HSQC spectrum analysis, and are respectively H1 and H2;
δ 2.28(6H, s) and 2.32(6H, s) were H25 and H26 and H36 and H37 by 1HNMR and HSQC spectroscopy, and detailed attribution was confirmed when HMBC was analyzed by the following carbon spectroscopy;
the delta 4.03/4.06(2H, t) and the 2.70/2.73(2H, t) are in the same system through 1HNMR, H-H COSY and HSQC spectrum analysis, and the delta 3.91/3.94(2H, t) and the delta 2.62/2.65(3H, t) are in the same system and are respectively 2 different O-substituted branched chains;
δ 5.49(1H, s) is H27;
δ 7.25/7.30(2H, m), 7.03/7.22(14H, m), 6.84/6.86(2H, d), 6.75/6.77(2H, d) and 6.54/6.56(2H, d) are 22H on the aromatic benzene ring, wherein δ 7.03/7.22(14H, m) and 6.84/6.86(2H, d) are known to be H on the same aromatic benzene ring by H-H COSY, and δ 6.75/6.77(2H, d) and 6.54/6.56(2H, d) are 4H on the same aromatic benzene ring, and the specific attribution will be detailed below by analysis of HMBC and NOESY spectra;
nuclear magnetic carbon spectrum (13C-NMR) data:
from the chemical shift values, the coupling constant values and the various two-dimensional spectra:
delta 55.84 is C27 by 13CNMR and HSQC atlas analysis, and delta 157.32 and 156.76 are C20 or C31 by induction effect, 13CNMR, NOESY and HMBC atlas analysis, and delta 157.32C has C-H remote correlation with delta 7.03/7.22(14H, m) and 6.84/6.86(2H, d) by HMBC atlas analysis, and delta 156.76C has C-H remote correlation with delta 6.75/6.77(2H, d) and 6.54/6.56(2H, d) to illustrate that 8H are H on O substituted aromatic benzene ring, and delta 156.76C has C-H remote correlation with C-H by C27 analysis, C27 has C-H remote correlation with delta 7.03/7.22(14H, m) only, so as to conclude that delta 157.32C is C31, delta 84 is C27, and delta 7 is C-H7.7H remote correlation with delta 7H, m, and delta 6342 is C7.7H 14H 7/7.7H 7H, m is C7H 14H, 14H 36/7H, and H33 is H7/d, delta 6.84/6.86(2H, d) is H30/H32, delta 6.75/6.77(2H, d) is H18/H22, and delta 6.54/6.56(2H, d) is H19/H21;
from the above identified H19 and H21 and H30 and H32, analyzing NOESY spectra we can confirm that H19 and H21 have NOE effect with δ 3.91/3.94(2H, t), and H30/H32 and δ 4.03/4.06(2H, t) have NOE effect, and thus δ 3.91/3.94(2H, t) can be determined as H23, δ 4.03/4.06(2H, t) as H34, and further confirm that δ 2.70/2.73(2H, t) as H35, δ 2.32(6H, s) as H36/H37, δ 2.62/2.65(3H, t) as H24, and δ 2.28(6H, s) as H25/H26;
according to the attribution H, the HSQC map is analyzed, and delta 13.66 and 29.01 are C1 and C2, delta 45.92 is C25 and C26, and C36 and C37, delta 58.32 and 58.35 are C24 and C35, and delta 65.68 and 65.93 are C23 and C34;
delta 144.39, 142.52, 142.33, 141.61, 141.37, 138.06, 136.29 and 135.68 are known as 8 quaternary carbons by HSQC spectra, and are specifically assigned as follows:
the C-H remote correlation between delta 135.68 and H19/H21(6.54/6.56ppm) is not existed in H18/H22(6.75/6.77ppm), the C of delta 135.68 is known to be C17, and the C has no C-H remote correlation with H2(2.45/2.50ppm), which can further confirm;
analysis of HMBC spectrum revealed that δ 138.06 has C-H long range correlation with H18/H22(6.75/6.77ppm) but not with H19/H21(6.54/6.56ppm) and is assigned as C10, and the carbon has C-H long range correlation with δ 7.03/7.22(14H, m), so that the other 2 Hs in δ 7.03/7.22(14H, m) are H12/H16, and the chemical shift value is in the range of 7.13-7.14 ppm;
the C-H remote correlation between delta 136.29 and H30/H32(6.84/6.86ppm) but not with H29/H33(7.03/7.22ppm) is assigned as C28, and the C-H remote correlation between the carbon and H27(5.49ppm) is further confirmed;
finally, the inventors demonstrated chemical shifts of H2, H12/H16 and H18/H22 by the analysis of hydrogen spectrum and carbon spectrum, and then found that H2(2.45/2.50ppm) has NOE effect with H12/H16(7.13/7.14ppm) and does not have NOE effect with H18/H22(6.75/6.77ppm) by NOESY spectrum, so that the synthesized compound was confirmed to be Z type.
Example 3 preparation of 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol Compound represented by the formula (4)
Substantially the same as in example 1 except that the reaction solvent used was different.
Dissolving a compound 2- (4-bromophenoxy) -N, N-dimethylethylamine (8.30g, 34.20mmol) and a compound 2- (4-bromophenyl) -1-phenylbutanone (10.0g, 33.10mmol) in 350ml of acetone, cooling to-58 ℃, then dropwise adding an N-butyllithium solution (2.5mol/L, 14.5mmol) to the solution, maintaining the temperature in a bottle to be not higher than-30 ℃, slowly raising the temperature to room temperature after the dropwise adding, reacting for 8 hours, extracting, drying and concentrating to dryness after the reaction is completed, wherein the concentrate is prepared by using petroleum ether: ethyl acetate 4:1 to obtain 12.05g of 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol as a compound in 77.9% yield.
EXAMPLE 4 preparation of tamoxifen related substances represented by formula (1)
Specifically, the same as in example 2, the difference from example 2 is that:
in the preparation of the compound of formula (5), the reaction temperature was 60 ℃ and the reaction time was 9 hours in example 4, while the reaction temperature was 45 ℃ and the reaction time was 10 hours in example 2;
in the preparation of the compound of formula (7), in example 4, the reaction temperature is minus 40 ℃ and the reaction time is 7.5 hours, while in example 2, the reaction temperature is minus 68 ℃ and the reaction time is 9 hours;
in the preparation of the crude product of formula (1), in example 4, the reaction temperature is 50 ℃ and the reaction time is 12 h; in example 2, the reaction temperature was 80 ℃ and the reaction time was 9 hours.
The specific steps of this example are as follows:
the method comprises the following steps: preparation of a Compound represented by the formula (5): 35.0ml of a 6mol/L aqueous hydrochloric acid solution was added to the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol (7.50g,16.10mmol), reacted at 60 ℃ for 9 hours, the reaction of the starting materials was monitored for completion, concentrated to dryness under reduced pressure, 100ml of water and 100ml of dichloromethane were added, pH 9.0 was adjusted with 8% sodium hydroxide solution, and extraction, drying and concentration were carried out to dryness to obtain 6.83g of the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene of the formula (5) as an oil, with a yield of 94.7%.
Step two: preparation of a Compound represented by the formula (7): dissolving 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene (6.50g, 14.47mmol) of a compound shown as a formula (5) and 4- [2- (dimethylamino) ethoxy ] benzophenone (3.90g,14.49mmol) of a compound shown as a formula (6) in 150ml of tetrahydrofuran, cooling to-40 ℃, slowly dropwise adding an n-butyllithium solution (2.50mol/L, 7.0ml), continuing to react for 7.5 hours after dropwise adding, then adding 100ml of saturated saline, extracting an aqueous phase by using 100ml of ethyl acetate, combining organic phases, drying and concentrating to dryness to obtain 10.0g of a crude product, and preparing and purifying the crude product by using a high performance liquid chromatograph, wherein the type and the manufacturer of a chromatographic column, the proportion composition, the flow rate and the detection wavelength of a mobile phase are used, The injection volume and the post-treatment were the same as in example 2, and 6.37g of the compound (7) of the formula (7) was finally obtained in yield: 68.8 percent.
Step three: preparation of tamoxifen related substance shown in formula (1)
Adding formic acid into the compound (5.0g,7.80mmol) of the formula (7), reacting at 50 ℃ for 12 hours, detecting that the raw materials are completely reacted, concentrating the solvent, adding 100ml of water and 150ml of dichloromethane, extracting, drying and concentrating to dryness to obtain 4.16g of a crude compound (1);
step four: the compound of the formula (1) obtained in the previous step is subjected to preparative separation
The type manufacturer of the chromatographic column, the proportion composition of the mobile phase, the flow rate, the detection wavelength, the sample introduction volume and the post-treatment mode are the same as those of the embodiment 2, the preparation is carried out at 45 ℃ and then the reduced pressure concentration is carried out, 8 percent NaOH solution is added to adjust the PH to be 9.0, 200ml of dichloromethane is added to carry out extraction, drying and concentration to be dry, and the obtained product is extracted by isopropanol: water 2: 1, and finally obtaining 2.87g of a pure product of the formula (1) in yield: 58.8 percent.
The assay demonstrated that the material obtained was identical to that of example 2.
The above description is only a few embodiments of the present invention and does not limit the scope of the present invention.
Claims (10)
1. A preparation method of tamoxifen related substances shown in a formula (1),
the preparation method is characterized by comprising the following preparation routes:
the preparation method comprises the following steps:
the method comprises the following steps: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol shown in a formula (4) under an acidic condition to obtain a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5);
step two: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5) with a compound 4- [2- (dimethylamino) ethoxy ] benzophenone shown in a formula (6) to obtain a compound shown in a formula (7);
step three: reacting a compound shown in a formula (7) under an acidic condition to obtain a crude product shown in a formula (1);
step four: and (3) purifying the crude tamoxifen related substance shown in the formula (1) to obtain a pure tamoxifen related substance shown in the formula (1).
2. The preparation method according to claim 1, comprising the following steps:
the method comprises the following steps: reacting a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol shown in a formula (4) under an acidic condition at 30-60 ℃ for 7-13 hours to obtain a compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in a formula (5);
step two: reacting 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutene shown in the formula (5) with 4- [2- (dimethylamino) ethoxy ] benzophenone shown in the formula (6) at the temperature of minus 30-78 ℃ for 4-12 hours by taking an aprotic solvent as a reaction solvent to obtain a compound shown in the formula (7); the molar ratio of the compound shown in the formula (5) to the compound shown in the formula (6) is 1: 1;
step three: reacting the compound shown in the formula (7) for 5-13 hours at the temperature of 30-90 ℃ under an acidic condition to obtain a crude product shown in the formula (1);
step four: the crude tamoxifen related substances in the formula (1) are prepared and separated through high performance liquid chromatography, concentrated after preparation, added with alkaline water solution with the concentration of 7-10% to adjust the pH = 8-11, then added with organic solvent to perform extraction, drying and concentration, and the obtained product is recrystallized to finally obtain pure tamoxifen related substances in the formula (1).
3. The method of claim 2,
in the first step, the acid is protonic acid, and is selected from one of hydrochloric acid, phosphoric acid and sulfuric acid, or a mixture of the two or more;
in the second step, the aprotic solvent is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF and DMSO;
in the third step, the acid is selected from formic acid, acetic acid or a mixture of the two;
in the fourth step, the used alkali is inorganic alkali, and is selected from one of sodium hydroxide, potassium hydroxide and sodium bicarbonate; the organic solvent is selected from one of ethyl acetate, dichloromethane and chloroform.
4. The method of claim 3,
in the first step, the acid is hydrochloric acid or sulfuric acid;
in the second step, the aprotic solvent is acetone, acetonitrile, tetrahydrofuran or a mixture of two or more of the acetone, the acetonitrile and the tetrahydrofuran;
in the third step, the acid is formic acid.
5. The method of claim 2,
in the first step, the reaction temperature is preferably 45 ℃, and the reaction time is preferably 10 hours;
in the second step, the reaction temperature is preferably-68 ℃, and the reaction time is preferably 9 h;
in the third step, the reaction temperature is preferably 80 ℃, and the reaction time is preferably 9 hours;
in the fourth step, the pH is preferably adjusted to be 8.5-9.5.
6. The method according to claim 1 or 2, wherein the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of formula (4) is synthesized by the following method:
dissolving the compound 2- (4-bromophenoxy) -N, N-dimethylethylamine of the formula (3) and the compound 2- (4-bromophenyl) -1-phenylbutanone of the formula (2) in an aprotic solvent for reaction to obtain the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4).
7. The method according to claim 6, wherein the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of formula (4) is synthesized by the following steps:
dissolving a compound 2- (4-bromophenoxy) -N, N-dimethylethylamine of a formula (3) and a compound 2- (4-bromophenyl) -1-phenylbutanone of a formula (2) in an aprotic solvent, cooling to minus 30-78 ℃, then dropwise adding an N-butyllithium solution, reacting for 5-12 hours after the addition is finished, adding water and dichloromethane after the reaction is completed, extracting, drying, concentrating to dryness, and recrystallizing the concentrate to obtain the compound 2- (4-bromophenyl) -1- (4- (2- (dimethylamino) ethoxy) phenyl) -1-phenylbutanol of the formula (4);
the molar ratio of the compound shown in the formula (3) to the compound shown in the formula (2) is 1: 1.
8. a process according to claim 7, wherein the aprotic solvent used is selected from one or more of dichloromethane, acetone, chloroform, tetrahydrofuran, acetonitrile, DMF and DMSO.
9. The method according to claim 8, wherein the aprotic solvent is selected from one or more of acetone, chloroform, tetrahydrofuran, and acetonitrile.
10. The process according to claim 8, characterized in that the recrystallization solvent used is petroleum ether V: and (3) ethyl acetate V = 3-5: 1.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1062901A (en) * | 1991-01-05 | 1992-07-22 | 上海第十二制药厂 | The novel process of not separating geometrical isomer direct production tamoxifen citrate |
| CN103992234A (en) * | 2014-06-11 | 2014-08-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of tamoxifen citrate E isomer |
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2020
- 2020-03-09 CN CN202010156159.8A patent/CN111362816B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1062901A (en) * | 1991-01-05 | 1992-07-22 | 上海第十二制药厂 | The novel process of not separating geometrical isomer direct production tamoxifen citrate |
| CN103992234A (en) * | 2014-06-11 | 2014-08-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of tamoxifen citrate E isomer |
Non-Patent Citations (1)
| Title |
|---|
| Synthesis of the E and 2 Isomers of the Antiestrogen Tamoxifen and Its Metabolite, Hydroxytamoxifen, in Tritium-Labeled Form;David W. Robertson等;《J.Org.Chem.》;19821231;第47卷;2387-2393 * |
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