CN120329325A - Venetola impurities and preparation method thereof - Google Patents
Venetola impurities and preparation method thereofInfo
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- CN120329325A CN120329325A CN202410028542.3A CN202410028542A CN120329325A CN 120329325 A CN120329325 A CN 120329325A CN 202410028542 A CN202410028542 A CN 202410028542A CN 120329325 A CN120329325 A CN 120329325A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The invention discloses a nature of vitamin A ill-organized and a preparation method thereof, which comprises the following steps that a compound III is taken as a raw material, and is subjected to condensation reaction with a compound II to obtain a compound I-1, and the compound III is subjected to self-condensation reaction to obtain a compound I-2.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a vitamin A ill-organized mass and a preparation method thereof.
Background
The combination of valneturab (Venetoclax,Only one can come) The Bcl-2 selective inhibitor is developed by both Aber and Roche, is granted breakthrough treatment by FDA in 2015, is approved by FDA in 2016 and is marketed for treating Acute Myelogenous Leukemia (AML) patients, chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL), is the only Bcl-2 selective inhibitor marketed globally at present, can exert a targeting effect, selectively bind and inhibit B-cell lymphoma factor-2 protein, and is helpful for restoring apoptosis of tumor cells.
On 12 th year 2020, valnemulin is marketed in China as a batch for the treatment of adult Acute Myeloid Leukemia (AML) patients who are ill-suited for strongly induced chemotherapy due to complications in combination with azacitidine, or who are newly diagnosed with age 75 years and older.
Currently, the synthetic route for the valneturacrat is as follows:
In the process of synthesizing the valneturab, we find that a compound II intermediate with an indole ring structure can be generated in the process of synthesizing the valneturab, meanwhile, the compound II can generate side reaction with a compound with a carboxylic acid structure III to generate a compound I-1, meanwhile, the compound III is condensed to generate a compound I-2, so that the purity of the valneturab bulk drug is influenced, the compound I-1 and the compound I-2 need to be controlled in the process of synthesizing the valneturab, and the compound I-1 and the compound I-2 need to be monitored in the process of synthesizing the valneturab, so that the quality of the valneturab bulk drug is controlled. The compound I-1 and the compound I-2 are impurities which are necessarily generated in the synthesis process of the valneturab, the content of the compounds is low in the synthesis process of the valneturab, the compounds are difficult to separate, no report on the impurity compounds I-1 and I-2 and the synthesis method thereof exists at present, the compound I-1 and the compound I-2 are difficult to obtain, corresponding reference substances are absent, and the impurities are difficult to detect qualitatively and quantitatively in the synthesis process of the valneturab.
Therefore, the impurities I-1 and I-2 are synthesized, and a preparation method for effectively obtaining the compound I-1 and the compound I-2 with high purity is developed, so that the impurities can be used as an impurity reference substance to perform impurity positioning and impurity control in the valnemulin raw material medicine.
Disclosure of Invention
The invention aims to overcome the defect of quality control of the vitamin A ill-organized in the prior art and provide an impurity compound I-1 and a compound I-2 generated in the vitamin A synthetic process and a preparation method thereof, wherein the method can obtain the compound I-1 and the compound I-2 with high purity and can be used as an impurity reference substance for impurity positioning and impurity control in the vitamin A bulk drug.
The compound III is used as a raw material and is subjected to condensation reaction with the compound II to obtain a compound I-1, and the compound III is subjected to self-condensation reaction to obtain a compound I-2.
The present invention provides a compound of structural formula I:
wherein R is hydrogen or methyl.
A process for the preparation of compound I-1 comprising:
The method comprises the steps of preparing a compound I-1, wherein in the step of preparing the compound I-1, the alkali is triethylamine or N, N-diisopropylethylamine, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, the catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole, the molar ratio of the compound II to the condensing agent to the catalyst is 1:0.9-1.1:2.0-3.0:1.0-2.0:0.2-0.5, the reaction temperature is 20-30 ℃, and the reaction solvent is tetrahydrofuran or dichloromethane.
A process for the preparation of compound I-2 comprising:
The method comprises the steps of preparing a compound I-2, wherein in the step of preparing the compound I-2, the alkali is triethylamine or N, N-diisopropylethylamine, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide or dicyclohexylcarbodiimide, the catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole, the molar ratio of the compound III, the condensing agent and the catalyst is 1:2.0-3.0:0.5-1:0.2-0.5, the reaction temperature is 20-30 ℃, and the reaction solvent is tetrahydrofuran or dichloromethane.
The compound III is used as a raw material and is subjected to condensation reaction with the compound II to obtain a compound I-1, and the compound III is subjected to self-condensation reaction to obtain a compound I-2.
The beneficial effects are that:
The invention provides a valnemulin ill-organized and a preparation method thereof, wherein a compound III is used as a raw material, and is subjected to condensation reaction with a compound II to obtain an impurity compound I-1, and the compound III is subjected to self-condensation reaction to obtain an impurity compound I-2. The method has the advantages of cheap and easily obtained raw materials, simple operation and mild reaction conditions, can effectively obtain the high-purity vitamin A ill-organized compound I-1 and the high-purity vitamin A ill-organized compound I-2, and provides a series of impurity reference substances for the whole process research of the vitamin A.
Abbreviations for the reactants referred to in the specification are as follows:
EDCI 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride;
DCC: dicyclohexylcarbodiimide;
DIC: diisopropylcarbodiimide;
DMAP 4-dimethylaminopyridine;
HOBt 1-hydroxybenzotriazole;
TEA, triethylamine;
DIEA: N, N-diisopropylethylamine;
THF: tetrahydrofuran;
MeOH: methanol;
DCM: dichloromethane.
Drawings
FIG. 1 is a chart showing the detection of the content of the impurity compound I-1 in example 1.
FIG. 2 is a graph showing the measurement of the content of impurity compound I-2 in valnemulin according to example 6.
Detailed Description
The invention will be further illustrated by the following examples, which are carried out on the basis of the technical solutions of the invention, and it should be understood that these examples are only intended to illustrate the invention and are not intended to limit the scope of the invention.
Example 1
Synthesis of Compound I-1:
10.0g (16.4 mmol,1.0 eq) of compound III, 9.63g (16.4 mmol,1.0 eq) of compound II, 100g (3.28 mmol,0.2 eq) of dichloromethane and 0.40g (3.28 mmol,0.2 eq) of 4.15g (41.1 mmol,2.5 eq) of triethylamine are added into a 250mL reaction bottle, after the dripping is finished, the system is dissolved, EDCI 3.g (16.4 mmol,1.0 eq) is slowly added, the reaction temperature is kept at 20-30 ℃, stirring is carried out for 16h, a new main point (DCM/MeOH: 15:1) is formed by TLC observation, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, stirring extraction is carried out, standing is carried out, an organic phase is reserved, and 22.63g is obtained after concentration. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 80:1 elution of compound III, DCM/MeOH: 60:1 elution of target compound I-1), 50 ℃ decompression concentration of the eluent, obtaining white solid, yield 2.71g, yield 15%, HPLC for inspection, purity greater than 90%.
1HNMR(CDCl3,400MHz)：δ9.246(s,0.96H),8.125(d,1.02H),7.911(d,1.14H),7.847(d,0.85H),7.761(d,0.94H),7.404(q,1.02H),7.308(t,1.88H),7.287(d,1.01H),7.257(q,4.07H),6.965(q,4.11H),6.65(d,2.10H),6.495(d,0.97H),6.427(t,0.90H),6.175(d,1.11H),5.321(s,1.13H),3.743(s,3.02H),3.151(t,8.85H),2.805(s,4.12H),2.339(d,9.09H),2.297(d,5.12H),2.068(s,4.23H),1.455(t,4.06H),0.973(s,14.06H);m/z[M]+：1139.53.
The measurement results of the impurity compound I-1 content detection are shown in Table 1 and FIG. 1:
The retention time of the impurity compound I-1 is 32.902min, which is not detected in the final product of the valnemulin, and provides an impurity reference substance for the valnemulin in the synthesis process.
Example 2
Synthesis of Compound I-1:
To a 250mL reaction flask, 10.0g (16.4 mmol,1.0 eq) of compound II (9.63 g (16.4 mmol,1.0 eq), 100g (8.20 mmol,0.5 eq) of methylene chloride and 1.00g (8.20 mmol,0.5 eq) of 4-dimethylaminopyridine were added uniformly, 5.30g (41.1 mmol,2.5 eq) of N, N-diisopropylethylamine was added dropwise, after that, the system was dissolved, 4.70g (24.7 mmol,1.5 eq) of EDCI was slowly added to keep the reaction temperature at 20-30 ℃, stirring was carried out for 16h, TLC was observed to generate a new principal point (DCM/MeOH: 15:1), 20mL of water, 20mL of DCM and 30mL of THF were added sequentially to the reaction system, followed by stirring extraction, standing, liquid separation, and concentration to obtain 22.63g. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 80:1 elution of compound III, DCM/MeOH: 60:1 elution of target compound I-1), 50 ℃ decompression concentration of the eluent, obtaining white solid, yield of 2.69g, yield of 15%, HPLC for inspection, purity of more than 90%.
1HNMR(CDCl3,400MHz)：δ9.246(s,0.96H),8.125(d,1.02H),7.911(d,1.14H),7.847(d,0.85H),7.761(d,0.94H),7.404(q,1.02H),7.308(t,1.88H),7.287(d,1.01H),7.257(q,4.07H),6.965(q,4.11H),6.65(d,2.I0H),6.495(d,0.97H),6.427(t,0.90H),6.175(d,1.11H),5.321(s,1.13H),3.743(s,3.02H),3.151(t,8.85H),2.805(s,4.12H),2.339(d,9.09H),2.297(d,5.12H),2.068(s,4.23H),1.455(t,4.06H),0.973(s,14.06H);m/z[M]+：1139.53.
Example 3
Synthesis of Compound I-1:
10.0g (16.4 mmol,1.0 eq) of compound III, 8.6g (14.76 mmol,0.9 eq) of compound II8.40 g (3.28 mmol,0.2 eq) of dichloromethane are added into a 250mL reaction bottle, the mixture is uniformly dispersed, 4.15g (41.1 mmol,2.5 eq) of triethylamine is started to be dropwise added, the system is completely dissolved, 6.76g (32.8 mmol,2.0 eq) of DCC is slowly added, the reaction temperature is kept at 20-30 ℃, the stirring reaction is carried out for 16h, a new main point (DCM/MeOH: 15:1) is generated, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, the mixture is stirred and extracted, the mixture is left stand, the organic phase is reserved, and 22.63g is concentrated. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 80:1 elution of compound III, DCM/MeOH: 60:1 elution of target compound I-1), 50 ℃ decompression concentration of the eluent, obtaining white solid, yield 2.72g, yield 15%, HPLC for inspection, purity greater than 90%.
1HNMR(CDCl3,400MHz)：δ9.246(s,0.96H),8.125(d,1.02H),7.911(d,1.14H),7.847(d,0.85H),7.761(d,0.94H),7.404(q,1.02H),7.308(t,1.88H),7.287(d,1.01H),7.257(q,4.07H),6.965(q,4.11H),6.65(d,2.10H),6.495(d,0.97H),6.427(t,0.90H),6.175(d,1.11H),5.321(s,1.13H),3.743(s,3.02H),3.151(t,8.85H),2.805(s,4.12H),2.339(d,9.09H),2.297(d,5.12H),2.068(s,4.23H),1.455(t,4.06H),0.973(s,14.06H);m/z[M]+：1139.53.
Example 4
Synthesis of Compound I-1:
10.0g (16.4 mmol,1.0 eq) of compound III, 9.63g (16.4 mmol,1.0 eq) of compound II, 100g (3.28 mmol,0.2 eq) of dichloromethane and 0.40g (3.28 mmol,0.2 eq) of 4-dimethylaminopyridine are added into a 250mL reaction bottle, 4.97g (49.2 mmol,3.0 eq) of triethylamine is added dropwise, the system is dissolved after the dripping, 3.12g (24.7 mmol,1.5 eq) of DIC is slowly added, the reaction temperature is kept at 20-30 ℃, stirring reaction is carried out for 16h, a new main point (DCM/MeOH: 15:1) is generated by TLC observation, 20mL of water, 20mL of DCM and 30mL of THF are added into the reaction system in sequence, stirring extraction is carried out, standing and liquid separation is carried out, and an organic phase is reserved, and 22.63g is obtained by concentration. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 80:1 elution of compound III, DCM/MeOH: 60:1 elution of target compound I-1), 50 ℃ decompression concentration of the eluent, obtaining white solid, yield 2.71g, yield 15%, HPLC for inspection, purity greater than 90%.
1HNMR(CDCl3,400MHz)：δ9.246(s,0.96H),8.125(d,1.02H),7.911(d,1.14H),7.847(d,0.85H),7.761(d,0.94H),7.404(q,1.02H),7.308(t,1.88H),7.287(d,1.01H),7.257(q,4.07H),6.965(q,4.11H),6.65(d,2.10H),6.495(d,0.97H),6.427(t,0.90H),6.175(d,1.11H),5.321(s,1.13H),3.743(s,3.02H),3.151(t,8.85H),2.805(s,4.12H),2.339(d,9.09H),2.297(d,5.12H),2.068(s,4.23H),1.455(t,4.06H),0.973(s,14.06H);m/z[M]+：1139.53.
Example 5
Synthesis of Compound I-1:
10.0g (16.4 mmol,1.0 eq) of compound III, 10.55g (18.04 mmol,1.1 eq) of compound II10.55g (18.04 mmol,1.1 eq) of tetrahydrofuran, 1.04g (4.92 mmol,0.3 eq) of HOBt are uniformly dispersed, 3.32g (32.8 mmol,2.0 eq) of triethylamine is started to be added dropwise, the system is dissolved completely after the dripping, 4.70g (24.7 mmol,1.5 eq) of EDCI is slowly added, the reaction temperature is kept at 20-30 ℃, the stirring reaction is carried out for 16h, a new main point (DCM/MeOH: 15:1) is formed by observation of TLC, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, stirring extraction is carried out, standing and separated, an organic phase is reserved, and 22.63g is obtained after concentration. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 80:1 elution of compound III, DCM/MeOH: 60:1 elution of target compound I-1), 50 ℃ decompression concentration of the eluent, obtaining white solid, yield of 2.69g, yield of 15%, HPLC for inspection, purity of more than 90%.
1HNMR(CDCl3,400MHz)：δ9.246(s,0.96H),8.125(d,1.02H),7.911(d,1.14H),7.847(d,0.85H),7.761(d,0.94H),7.404(q,1.02H),7.308(t,1.88H),7.287(d,1.01H),7.257(q,4.07H),6.965(q,4.11H),6.65(d,2.I0H),6.495(d,0.97H),6.427(t,0.90H),6.175(d,1.11H),5.321(s,1.13H),3.743(s,3.02H),3.151(t,8.85H),2.805(s,4.12H),2.339(d,9.09H),2.297(d,5.12H),2.068(s,4.23H),1.455(t,4.06H),0.973(s,14.06H);m/z[M]+：1139.53.
Example 6
Synthesis of Compound I-2:
2.0g (3.29 mmol,1.0 eq) of compound III, 20mL of dichloromethane, 0.08g (0.66 mmol,0.2 eq) of 4-dimethylaminopyridine are added into a 50mL reaction bottle and uniformly dispersed, 0.83g (8.23 mmol,2.5 eq) of triethylamine is started to be added dropwise, 0.25g (1.65 mmol,0.5 eq) of EDCI is slowly added after the dropwise addition, the reaction temperature is kept at 20-30 ℃, stirring reaction is carried out for 16h, a new main point (DCM/MeOH: 15:1) is generated by TLC observation, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, the extraction liquid is separated, and the organic phase is concentrated to obtain 2.63g. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 40:1 elution of compound III, DCM/MeOH: 20:1 elution of target compound I-2), 50 ℃ reduced pressure concentration of the eluent, obtaining concentrate, with DCM 20mL and water 20mL stirring and dissolving, with 1N hydrochloric acid to adjust aqueous phase pH=3, separating organic phase, repeated washing and acid adjustment operation once, obtaining organic phase, 50 ℃ reduced pressure concentration to obtain white solid, yield of 0.71g, yield 39%, sending to HPLC, purity greater than 90%.
1HNMR(DMSO-D6,400MHz)：δ12.158(s,0.83H),11.626(s,0.91H),7.986(s,1.00H),7.979(s,1.89H)7.870(d,0.96H),7.485(d,1.99H),7.396(s,1.05H),7.356(t,4.13H),7.054(q,3.85H),6.809(d,1.89H),6.785(t,0.86H),6.645(s,0.81H),6.333(s,0.95H),5.762(s,0.84H),3.155(s,2.83H),3.106(s,2.98H),2.741(s,3.22H),2.180(s,9.26H),1.964(s,3.27H),1.400(s,3.16H),0.939(d,12.04H).(1/2)m/z[M]+：563.09.
The measurement results of the content detection of the impurity compound I-2 in the valneturab are shown in table 2 and fig. 2:
Example 7
Synthesis of Compound I-2:
2.0g (3.29 mmol,1.0 eq) of compound III, 20mL of dichloromethane, 0.08g (0.66 mmol,0.2 eq) of 4-dimethylaminopyridine are added into a 50mL reaction bottle and uniformly dispersed, 1.27g (9.87 mmol,3.0 eq) of N, N-diisopropylethylamine is added dropwise, 0.25g (1.65 mmol,0.5 eq) of EDCI is slowly added after the dropwise, the reaction temperature is kept between 20 ℃ and 30 ℃, stirring reaction is carried out for 16h, a new main point (DCM/MeOH: 15:1) is generated by TLC observation, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, the organic phase is concentrated to obtain 2.63g. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 40:1 elution of compound III, DCM/MeOH: 20:1 elution of target compound I-2), 50 ℃ reduced pressure concentration of the eluent, obtaining concentrate, with DCM 20mL and water 20mL stirring and dissolving, with 1N hydrochloric acid to adjust aqueous phase pH=3, separating organic phase, repeated washing and acid adjustment operation once, obtaining organic phase, 50 ℃ reduced pressure concentration to obtain white solid, yield of 0.70g, yield 39%, sending to HPLC, purity greater than 90%.
1HNMR(DMSO-D6,400MHz)：δ12.158(s,0.83H),11.626(s,0.91H),7.986(s,1.00H),7.979(s,1.89H)7.870(d,0.96H),7.485(d,1.99H),7.396(s,1.05H),7.356(t,4.13H),7.054(q,3.85H),6.809(d,1.89H),6.785(t,0.86H),6.645(s,0.81H),6.333(s,0.95H),5.762(s,0.84H),3.155(s,2.83H),3.106(s,2.98H),2.741(s,3.22H),2.180(s,9.26H),1.964(s,3.27H),1.400(s,3.16H),0.939(d,12.04H).(1/2)m/z[M]+：563.09.
Example 8
Synthesis of Compound I-2:
2.0g (3.29 mmol,1.0 eq) of compound III, 20mL of dichloromethane, 0.2g (1.65 mmol,0.5 eq) of 4-dimethylaminopyridine are added into a 50mL reaction bottle and uniformly dispersed, 0.67g (6.58 mmol,2.0 eq) of triethylamine is started to be dropwise added, 0.34g (1.65 mmol,0.5 eq) of DCC is slowly added into the system after dropwise addition, the reaction temperature is kept at 20-30 ℃, stirring reaction is carried out for 16h, TLC observation generates a new main point (DCM/MeOH: 15:1), 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, the extraction liquid is separated, and the organic phase is concentrated to obtain 2.63g. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 40:1 elution of compound III, DCM/MeOH: 20:1 elution of target compound I-2), 50 ℃ reduced pressure concentration of the eluent, obtaining concentrate, with DCM 20mL and water 20mL stirring and dissolving, with 1N hydrochloric acid to adjust aqueous phase pH=3, separating organic phase, repeated washing and acid adjustment operation once, obtaining organic phase, 50 ℃ reduced pressure concentration to obtain white solid, yield of 0.70g, yield 39%, sending to HPLC, purity greater than 90%.
1HNMR(DMSO-D6,400MHz)：δ12.158(s,0.83H),11.626(s,0.91H),7.986(s,1.00H),7.979(s,1.89H)7.870(d,0.96H),7.485(d,1.99H),7.396(s,1.05H),7.356(t,4.13H),7.054(q,3.85H),6.809(d,1.89H),6.785(t,0.86H),6.645(s,0.81H),6.333(s,0.95H),5.762(s,0.84H),3.155(s,2.83H),3.106(s,2.98H),2.741(s,3.22H),2.180(s,9.26H),1.964(s,3.27H),1.400(s,3.16H),0.939(d,12.04H).(1/2)m/z[M]+：563.09.
Example 9
Synthesis of Compound I-2:
2.0g (3.29 mmol,1.0 eq) of compound III, 20mL of tetrahydrofuran, 0.14g (0.66 mmol,0.2 eq) of HOBt are uniformly dispersed, 0.83g (8.23 mmol,2.5 eq) of triethylamine is started to be added dropwise, 0.41g (3.29 mmol,1.0 eq) of DIC is slowly added after the dropwise addition, the reaction temperature is kept at 20-30 ℃, stirring reaction is carried out for 16 hours, a new main point (DCM/MeOH: 15:1) is generated by observing by TLC, 20mL of water, 20mL of DCM and 30mL of THF are sequentially added into the reaction system, the extract liquid is separated, and the organic phase is concentrated to obtain 2.63g. Sand column chromatography separation (column chromatography conditions: 20w/w silica gel column (200-300 mesh), DCM/MeOH: 100:1 removal of small polar impurities, DCM/MeOH: 40:1 elution of compound III, DCM/MeOH: 20:1 elution of target compound I-2), 50 ℃ reduced pressure concentration of the eluent, obtaining concentrate, with DCM 20mL and water 20mL stirring and dissolving, with 1N hydrochloric acid to adjust aqueous phase pH=3, separating organic phase, repeated washing and acid adjustment operation once, obtaining organic phase, 50 ℃ reduced pressure concentration to obtain white solid, yield of 0.71g, yield 39%, sending to HPLC, purity greater than 90%.
1HNMR(DMSO-D6,400MHz)：δ12.158(s,0.83H),11.626(s,0.91H),7.986(s,1.00H),7.979(s,1.89H)7.870(d,0.96H),7.485(d,1.99H),7.396(s,1.05H),7.356(t,4.13H),7.054(q,3.85H),6.809(d,1.89H),6.785(t,0.86H),6.645(s,0.81H),6.333(s,0.95H),5.762(s,0.84H),3.155(s,2.83H),3.106(s,2.98H),2.741(s,3.22H),2.180(s,9.26H),1.964(s,3.27H),1.400(s,3.16H),0.939(d,12.04H).(1/2)m/z[M]+：563.09.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (9)
1. A compound of structural formula (I):
wherein R is hydrogen or methyl.
2. A process for the preparation of compound I according to claim 1, characterized in that:
Wherein in the step of preparing the compound I-1, the alkali is triethylamine or N, N-diisopropylethylamine, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide or dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole.
3. The method for preparing a compound I according to claim 2, wherein in the step of preparing the compound I-1, the molar ratio of the compound III to the compound II to the base to the condensing agent to the catalyst is 1:0.9-1.1:2-3:1-2:0.2-0.5.
4. The method for producing compound I according to claim 2, wherein the reaction temperature in the step of producing compound I-1 is 20 to 30 ℃.
5. The process for preparing compound I according to claim 2, wherein the reaction solvent in the step of preparing compound I-1 is tetrahydrofuran or methylene chloride.
6. A process for the preparation of compound I according to claim 1, characterized in that:
Wherein in the step of preparing the compound I-2, the alkali is triethylamine or N, N-diisopropylethylamine, the condensing agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, diisopropylcarbodiimide or dicyclohexylcarbodiimide, and the catalyst is 4-dimethylaminopyridine or 1-hydroxybenzotriazole.
7. The method of preparing compound I according to claim 6, wherein the molar ratio of compound III to alkali to condensing agent to catalyst in the step of preparing compound I-2 is 1:2 to 3:0.5 to 1:0.2 to 0.5.
8. The method for producing compound I according to claim 6, wherein the reaction temperature in the step of producing compound I-2 is 20 to 30 ℃.
9. The process for preparing compound I according to claim 6, wherein in the step of preparing compound I-2, the reaction solvent is tetrahydrofuran or methylene chloride.
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