CN110117255A - A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof - Google Patents
A kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof Download PDFInfo
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- CN110117255A CN110117255A CN201910497577.0A CN201910497577A CN110117255A CN 110117255 A CN110117255 A CN 110117255A CN 201910497577 A CN201910497577 A CN 201910497577A CN 110117255 A CN110117255 A CN 110117255A
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- buddhist nun
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
Present invention firstly discovers that a kind of pleasure is cut down for Buddhist nun's impurity, it is C that the pleasure, which is cut down for Buddhist nun's impurity molecule formula,20H18N4O4, structural formula is Formulas I.The present invention also provides above-mentioned pleasures to cut down for the preparation method of Buddhist nun's impurity, comprising the following steps: 1) using Pd/C as catalyst, under hydrogen effect, happy cut down generates the intermediate that structural formula is Formula II for Buddhist nun's dechlorination；2) under the action of an acid, structural formula is the intermediate demethylation of Formula II, obtains pleasure and cuts down for Buddhist nun's impurity.The present invention can stablize, high yield and high-purity composite structure formula be that the pleasure of Formulas I is cut down for Buddhist nun's impurity, which can be used as impurity reference substance and carries out stringent, accurate quality monitoring to happy cut down for the preparation process of Buddhist nun.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of pleasure is cut down for Buddhist nun's impurity and preparation method thereof.
Background technique
Happy to cut down for Buddhist nun (Lenvatinib), chemical name is 4- [3- chloro- 4- (cyclopropylaminocarbonyl) amino-benzene oxygen]-
7- methoxyl group -6- quinoline formyl amine, molecular formula C21H19ClN4O4, CAS registration number 417716-92-8, structural formula is as follows:
Happy cut down for Buddhist nun is a kind of new oral multiple target point tyrosine kinase inhibition that the research and development of material (Eisai) company are defended by Japan
Agent, the medicine are approved by the fda in the United States for liver cancer, thyroid cancer and advanced renal cell carcinoma treatment.In September, 2018, happy cut down exist for Buddhist nun
The granted listing of China has been the most widely used first-line drug of liver cancer treatment at present for the targeted therapy of liver cancer.
Currently, being prepared with a large amount of technological accumulation for happy cut down for the production of Buddhist nun.Such as Publication No. " CN109044977A ",
The Chinese patent of entitled " a kind of pleasure cut down for Buddhist nun's solid dispersions and preparation method thereof and preparation "；Publication No.
" CN105801481A ", the Chinese patent of entitled " a kind of pleasure cut down the synthetic method for Buddhist nun "；Publication No.
" CN105985289A ", the Chinese patent of entitled " a kind of pleasure cut down the preparation method for Buddhist nun "；And Publication No.
" CN108623521A ", the patents such as the Chinese patent of entitled " a kind of pleasure cut down the preparation method for Buddhist nun ", discloses various
The happy preparation process cut down for Buddhist nun of preparation.Publication No. " CN108623521A ", entitled " a kind of pleasure is cut down for the preparation side of Buddhist nun
Preparation process disclosed in the Chinese patent of method ", working condition is simpler, and yield, purity are higher.
It is entitled " a kind of pleasure cut down the preparation method for Buddhist nun " but according to Publication No. " CN108623521A "
Chinese patent disclosed in preparation process when producing happy cut down for Buddhist nun, as shown in figure 4, can be apparent miscellaneous containing one in finished product
Matter, above-mentioned impurity can generate strong influence to the efficacy and saferry of drug.In most cases, the impurity in drug can reduce
The curative effect of drug influences the stability of drug and the toxic side effect of significantly increasing medicament.Foot is also lacked for above-mentioned impurity at present
Enough research.
Summary of the invention
The present invention for the technical problems in the prior art, provides a kind of pleasure and cuts down for Buddhist nun's impurity and preparation method thereof,
It can stablize, synthesize the impurity to high yield and high-purity, which can be used as impurity reference substance to the happy preparation cut down for Buddhist nun
Cheng Jinhang is stringent, accurate quality monitoring.
The technical scheme to solve the above technical problems is that a kind of pleasure is cut down for Buddhist nun's impurity, the pleasure is cut down miscellaneous for Buddhist nun
Matter molecular formula is C20H18N4O4, structural formula is Formulas I:
The present invention also provides the preparation method of above-mentioned impurity, technical solution is as follows: a kind of above-mentioned pleasure is cut down for Buddhist nun's impurity
Preparation method is synthesized using following reaction route:
The following steps are included:
1) using Pd/C as catalyst, under hydrogen effect, happy cut down generates the intermediate that structural formula is Formula II for Buddhist nun's dechlorination；
2) under the action of an acid, structural formula is the intermediate demethylation of Formula II, obtains pleasure and cuts down for Buddhist nun's impurity.
Based on the above technical solution, the present invention can also be improved as follows.
Further, the step 1) the following steps are included:
1. happy cut down is mixed in Buddhist nun, the first organic solvent and Pd/C catalyst addition reaction flask；
2. being continually fed into hydrogen into reaction flask, make the reaction that dechlorination occurs in reaction flask, until happy cut down all disappears for Buddhist nun
It loses；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, the intermediate that structural formula is Formula II is obtained.
Further, the step 1. in, happy cut down for the addition mass ratio of Buddhist nun and Pd/C catalyst is 1:0.05~0.20.
Further, first organic solvent is methanol, in ethyl alcohol, tetrahydrofuran, acetonitrile, n,N-Dimethylformamide
It is one or more of；The additional amount of first organic solvent is that every gram of pleasure is cut down for Buddhist nun's addition the first solvent of 5~50mL.
Further, the step 2. in, reaction temperature be 10~50 DEG C.
Further, the step 2) the following steps are included:
1. structural formula is that the intermediate of Formula II and the second solvent are added in reaction flask, to reaction flask under lasting stirring condition
Middle addition acid；
2. reaction flask is heated up to 0~100 DEG C, make the liquid reactions in reaction flask, until structural formula is the centre of Formula II
Body completely disappears；
3. 2. reaction solution that step is obtained filters or extraction, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, obtains pleasure and cut down for Buddhist nun's impurity.
Further, second solvent is 1,2- dichloroethanes, methylene chloride, chloroform, toluene, acetonitrile, methanol and ethyl alcohol
One or more of；The additional amount of second solvent is that 5~20mL second is added in the intermediate that every gram of structural formula is Formula II
Solvent.
Further, the acid be one of Boron tribromide, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, alchlor and acetic acid or
It is several；The structural formula of the addition is the intermediate of Formula II and the molar ratio of acid is 1:1~10.
Further, the reaction temperature of the step 2. is 10~80 DEG C.
The beneficial effects of the present invention are: compared with prior art, the present invention provides a kind of new pleasures to cut down for Buddhist nun's impurity, and
Structural confirmation is carried out, so as to carry out accurate quantitative analysis to happy cut down for the content of the impurity in Buddhist nun, to help to produce
To the accurate control of the impurity content in journey, to monitor the quality of production, promotes production technology and provide research foundation；Of the invention
Preparation method can stablize, synthesize the impurity to high yield and high-purity, provide raw material basis to further investigate its safety.
Detailed description of the invention
Fig. 1 is that pleasure of the invention cuts down the nuclear magnetic resonance spectroscopy spectrogram for Buddhist nun's impurity；
Fig. 2 is that pleasure of the invention cuts down the carbon-13 nmr spectra spectrogram for Buddhist nun's impurity；
Fig. 3 is that pleasure of the invention is cut down for the mass spectrogram of Buddhist nun's impurity；
Fig. 4 is that the pleasure of art methods preparation cuts down the HPLC spectrogram for Buddhist nun；
Fig. 5 is that pleasure prepared by the embodiment of the present invention 5 cuts down the HPLC spectrogram for Buddhist nun's impurity.
Specific embodiment
The principles and features of the present invention are described below, and the given examples are served only to explain the present invention, is not intended to limit
Determine the scope of the present invention.
The present invention provides a kind of pleasures to cut down for Buddhist nun's impurity, and it is C that the pleasure, which is cut down for Buddhist nun's impurity molecule formula,20H18N4O4, structural formula
For Formulas I:
The present inventor is according to Publication No. " CN108623521A ", and entitled " a kind of pleasure is cut down for Buddhist nun's
Technical study documented by the Chinese patent of preparation method " is happy when cutting down the preparation for Buddhist nun, using various analysis means to product into
It has gone and has largely researched and analysed, it is found that in final product that molecular structure should there are a relatively stable compound impurities
It is cut down with pleasure quite similar for Buddhist nun.Above-mentioned impurity and happy cut down through great efforts, are finally successfully separated, and to its molecule by inventor for Buddhist nun
Structure is studied, it is determined that the molecular structure of the impurity such as Formulas I.
For the ease of carrying out follow-up study, inventor is cut down for Buddhist nun as raw material using pleasure, by the method for reverse reaction, is developed
It can stablize and prepare above-mentioned pleasure and cut down for the preparation method of Buddhist nun's impurity, be synthesized using following reaction route:
The following steps are included:
1) using Pd/C as catalyst, under hydrogen effect, happy cut down generates the intermediate that structural formula is Formula II for Buddhist nun's dechlorination；
2) under the action of an acid, structural formula is the intermediate demethylation of Formula II, obtains pleasure and cuts down for Buddhist nun's impurity.
In some preferred embodiments, happy cut down for the mass ratio of Buddhist nun and Pd/C is 1:0.05~0.20, preferably 1:
0.08~0.10, within the scope of the amount ratio, it not only can guarantee that reaction sufficiently carries out, but also can avoid the waste of Pd/C.
The present invention also provides improved technical solutions, and in improved technical solution, pleasure of the invention is cut down for Buddhist nun's impurity
Preparation method can using detailed step below prepare.
Structural formula is the preparation of the intermediate of Formula II:
1. happy cut down is mixed in Buddhist nun, the first organic solvent and Pd/C catalyst addition reaction flask；
2. being continually fed into hydrogen into reaction flask, make the reaction that dechlorination occurs in reaction flask, until happy cut down all disappears for Buddhist nun
It loses；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, the intermediate that structural formula is Formula II is obtained.
Pleasure is cut down for the preparation of Buddhist nun's impurity:
1. structural formula is that the intermediate of Formula II and the second solvent are added in reaction flask, to reaction flask under lasting stirring condition
Middle addition acid；
2. reaction flask is heated up to 0~100 DEG C, make the liquid reactions in reaction flask, until structural formula is the centre of Formula II
Body completely disappears；
3. 2. reaction solution that step is obtained filters or extraction, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, obtains pleasure and cut down for Buddhist nun's impurity.
There is also preferred embodiments for above scheme.
In a preferred embodiment, the preferred methanol of the first organic solvent, ethyl alcohol, tetrahydrofuran, acetonitrile, N, N- dimethyl
The mixing of one or more of formamide.
In a preferred embodiment, every gram of pleasure, which is cut down, is added the first organic solvent of 5~50mL for Buddhist nun.In the amount ratio range
It is interior, happy cut down can be made to be substantially dissolved in the first organic solvent for Buddhist nun, avoid waste of solvent.
In a preferred embodiment, preferably 10~50 DEG C of the reaction temperature of the reaction of dechlorination.Inventor the study found that
Under the conditions of above-mentioned temperature, structural formula obtained is that the yield of the intermediate of Formula II is higher.
In a preferred embodiment, the second solvent preferably 1,2- dichloroethanes, methylene chloride, chloroform, toluene, acetonitrile,
The mixing of one or more of methanol and ethyl alcohol.
In a preferred embodiment, every gram of structural formula is that the second solvent of 5~20mL is added in the intermediate of Formula II.In the use
Amount is than that can make intermediate be substantially dissolved in the second solvent, avoid waste of solvent in range.
In a preferred embodiment, acid preferably Boron tribromide, hydrochloric acid, hydrobromic acid, trifluoroacetic acid, alchlor and acetic acid
One or more of mixing.Using above-mentioned sour reaction efficiency highest, and react the most complete.
In a preferred embodiment, structural formula is the intermediate of Formula II and preferred 1:1~10 of molar ratio of acid.It rubs herein
You than in range, obtain it is happy cut down it is higher for the yield of Buddhist nun's impurity.
In a preferred embodiment, preparation pleasure is cut down for preferably 0~100 DEG C of reaction temperature of Buddhist nun's impurity.Inventor's research
It was found that pleasure obtained is cut down higher for the yield of Buddhist nun's impurity in this temperature range.
The present invention detects the monitoring of each reaction process using conventional method in the art, including TLC, HPLC or
NMR etc., generally using the disappearance of raw material as reaction end.
The embodiment of the present invention preferably carries out column chromatographic purifying: C18 bonded silica gel column (Waters using following parameter
C18,4.6mm × 250mm, 5 μm of Symmetry equal columns), mobile phase A: 10mM NaH2PO4, pH=5.6；Mobile phase B: acetonitrile.
The parameter for carrying out gradient elution is shown in Table 1.Flow velocity is 1.0mL/min, and column temperature is 30 DEG C, Detection wavelength 230nm.
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 85 | 15 |
| 5 | 85 | 15 |
| 15 | 50 | 50 |
| 25 | 10 | 90 |
| 33 | 10 | 90 |
| 33.01 | 85 | 15 |
| 38 | 85 | 15 |
1 elution parameters of table
Embodiment 1:
This implementation column provides a kind of preparation method for the intermediate that structural formula is Formula II, and specific synthetic route is as follows:
It is prepared with the following method:
1. cutting down happy for Buddhist nun (3.0g, 7.0mmol), Pd/C (0.3g) and methanol (30mL) are added in reaction flask and mix；
2. hydrogen balloon and water pump is used three times, to be then stirred to react system pump drainage at 10 DEG C, TLC detection is until pleasure is cut down
For Buddhist nun's disappearance；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=40:1, v/v), tied
Structure formula is the intermediate of Formula II.
Product 2.6g, yield 94% are obtained using the method for the present embodiment.
As shown in FIG. 1 to 3, related data is as follows is identified to intermediate obtained in the present embodiment:
ESI-MS (m/z): 393.2；
1H NMR(500MHz,DMSO-d6):δ8.65(s,1H),8.60(s,1H),8.45(s,1H),7.85(s,1H),
7.71 (s, 1H), 7.50 (d, J=7.9Hz, 2H), 7.46 (s, 1H), 7.13 (d, J=7.9Hz, 2H), 6.40-6.45 (m,
2H),3.92(s,3H),2.41-2.46(m,1H),0.63(s,2H),0.41(s,2H)。
Embodiment 2:
This implementation column provides a kind of preparation method for the intermediate that structural formula is Formula II, is made with the following method
It is standby:
1. cutting down happy for Buddhist nun (2.8g, 7.0mmol), Pd/C (0.3g) and tetrahydrofuran (30mL) are added in reaction flask and mix
It closes；
2. hydrogen balloon and water pump is used three times, to be then stirred to react system pump drainage at 50 DEG C, TLC detection is until pleasure is cut down
For Buddhist nun's disappearance；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=40:1, v/v), tied
Structure formula is the intermediate of Formula II.
Product 2.0g, yield 78% are obtained using this method.
Embodiment 3:
This implementation column provides a kind of preparation method for the intermediate that structural formula is Formula II, is made with the following method
It is standby:
1. cutting down happy for Buddhist nun (2.5g, 5.9mmol), reaction is added in Pd/C (0.3g) and n,N-Dimethylformamide (15mL)
It is mixed in bottle；
2. hydrogen balloon and water pump is used three times, to be then stirred to react system pump drainage at 20 DEG C, TLC detection is until pleasure is cut down
For Buddhist nun's disappearance；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=40:1, v/v), tied
Structure formula is the intermediate of Formula II.
Product 1.9g, yield 83% are obtained using this method.
Embodiment 4:
This implementation column provides a kind of preparation method for the intermediate that structural formula is Formula II, is made with the following method
It is standby:
1. cutting down happy for Buddhist nun (2.3g, 5.4mmol), Pd/C (0.2g) and ethyl alcohol (28mL) are added in reaction flask and mix；
2. hydrogen balloon and water pump is used three times, to be then stirred to react system pump drainage at 40 DEG C, TLC detection is until pleasure is cut down
For Buddhist nun's disappearance；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=40:1, v/v), tied
Structure formula is the intermediate of Formula II.
Product 1.8g, yield 85% are obtained using this method.
Embodiment 5:
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, and specific synthetic route is as follows:
It is prepared with the following method:
1. the intermediate (2.0g, 5.1mmol) that structural formula is Formula II is dissolved in 1,2- dichloroethanes (12mL), then stirring
Boron tribromide (1.9g, 7.6mmol) is added dropwise under the conditions of mixing；
2. continuing to be stirred to react 2h at 0 DEG C, TLC detection is until the intermediate that structural formula is Formula II disappears；
3. 2. reaction solution pH that step obtains is adjusted to 7, organic layer is separated, water layer is extracted twice using methylene chloride
(10mL × 2) merge organic layer, dry, filter, evaporating solvent under reduced pressure obtains crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.8g, yield 93%, purity 99.0% are obtained using this method.
Pleasure obtained in the present embodiment is cut down and is identified for Buddhist nun's impurity, as shown in figure 5, related data is as follows:
ESI-MS (m/z): 379.3；
1H NMR (400MHz, DMSO-d6): δ 11.26 (s, 1H), 8.97 (d, J=6.5Hz, 1H), 8.70 (s, 1H),
8.33 (d, J=9.1Hz, 1H), 8.07 (s, 1H), 7.93 (d, J=25.1Hz, 2H), 7.70 (s, 1H), 7.62 (s, 1H),
7.35 (d, J=8.8Hz, 1H), 7.27 (s, 1H), 6.95 (d, J=6.5Hz, 1H), 6.74 (s, 1H), 2.56 (s, 1H), 0.64
(s,2H),0.42(s,2H)。
13C NMR(101MHz,DMSO-d6):δ167.90,165.23,161.59,155.86,148.40,146.47,
142.87,136.22,128.66,125.75,122.41,120.80,114.49,104.02,101.06,22.81,6.65。
Embodiment 6:
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, specifically prepares with the following method:
1. the intermediate (1.9g, 4.8mmol) that structural formula is Formula II is dissolved in methylene chloride (38mL), then in stirring bar
Alchlor (3.2g, 24.2mmol) is added portionwise under part；
2. continuing to be stirred to react 1.5h at 20 DEG C, TLC detection is until intermediate disappears；
3. 2. reaction solution that step is obtained is poured slowly into ice water (60mL), 30min is stirred, system pH is adjusted to 7, point
Organic layer out, water layer are extracted twice (20mL × 2) using methylene chloride, merge organic layer, dry, are filtered, evaporating solvent under reduced pressure,
Obtain crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.4g, yield 76%, purity 98.6% are obtained using this method.
Embodiment 7:
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, specifically prepares with the following method:
1. the intermediate (2.2g, 5.6mmol) that structural formula is Formula II is dissolved in ethyl alcohol acetonitrile (28mL), then in stirring bar
85% concentrated hydrochloric acid (22mL) is added dropwise under part；
2. continuing to be stirred to react 1.2h at 40 DEG C, TLC detection is until intermediate disappears；
3. 2. reaction solution that step is obtained is poured slowly into ice water (60mL), 30min is stirred, system pH is adjusted to 7, this
When have solid precipitation, continue to stir 15min, filter, filter cake is washed with water, and is dried in vacuo, obtains crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.5g, yield 71%, purity 98.2% are obtained using this method.
Embodiment 8:
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, specifically prepares with the following method:
1. the intermediate (1.7g, 4.3mmol) that structural formula is Formula II is dissolved in ethyl alcohol (10mL), then under agitation
It is added dropwise hydrobromic acid (48%, 4.9mL, 43.0mmol)；
2. continuing to be stirred to react 1.8h at 100 DEG C, TLC detection is until intermediate disappears；
3. 2. reaction solution that step is obtained is poured slowly into ice water (60mL), 30min is stirred, system pH is adjusted to 7, this
When have solid precipitation, continue to stir 15min, filter, filter cake is washed with water, dry, obtains crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.0g, yield 61%, purity 98.6% are obtained using this method.
Embodiment 9:
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, specifically prepares with the following method:
1. the intermediate (1.5g, 3.8mmol) that structural formula is Formula II is dissolved in chloroform (8mL), then in stirring condition
Lower dropwise addition trifluoroacetic acid (2.8mL, 38.2mmol)；
2. continuing to be stirred to react 2.6h at 60 DEG C, TLC detection is until intermediate disappears；
3. system pH is adjusted to 7 by 2. reaction solution that step obtains, organic layer is separated, water layer makes to be extracted with dichloromethane two
Secondary (20mL × 2) merge organic layer, dry, filter, evaporating solvent under reduced pressure obtains crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.2g, yield 83%, purity 98.4% are obtained using this method.
Embodiment 10
Implementation column of the invention provides a kind of pleasure and cuts down for the preparation method of Buddhist nun's impurity, specifically prepares with the following method:
1. the intermediate (2.1g, 5.5mmol) that structural formula is Formula II is dissolved in toluene (32mL), then under agitation
It is added dropwise acetic acid (3.0mL, 36.5mmol)；
2. continuing to be stirred to react 1.6h at 80 DEG C, TLC detection is until intermediate disappears；
3. system pH is adjusted to 7 by 2. reaction solution that step obtains, organic layer is separated, water layer makes to be extracted with dichloromethane two
Secondary (20mL × 2) merge organic layer, dry, filter, evaporating solvent under reduced pressure obtains crude product；
4. 3. crude product that step is obtained carries out column chromatographic purifying (methylene chloride/methanol=30:1, v/v), tied
Structure formula is that the pleasure of Formulas I is cut down for Buddhist nun's impurity.
Product 1.8g, yield 82%, purity 98.1% are obtained using this method.
Pleasure prepared by 5~embodiment of the embodiment of the present invention 10, which is cut down, can be used as impurity reference substance for Buddhist nun's impurity, to help to give birth to
To the accurate control of the impurity content during production, the quality of production is improved.Simultaneously, moreover it is possible to cut down for further investigation pleasure for Buddhist nun's impurity
The drug safeties Journal of Sex Research such as biological safety provides raw material basis.
The foregoing is merely presently preferred embodiments of the present invention, is not intended to limit the invention, it is all in spirit of the invention and
Within principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of pleasure is cut down for Buddhist nun's impurity, which is characterized in that it is C that the pleasure, which is cut down for Buddhist nun's impurity molecule formula,20H18N4O4, structural formula is formula
I:
2. a kind of pleasure described in claim 1 is cut down for the preparation method of Buddhist nun's impurity, which is characterized in that closed using following reaction route
At:
The following steps are included:
1) using Pd/C as catalyst, under hydrogen effect, happy cut down generates the intermediate that structural formula is Formula II for Buddhist nun's dechlorination；
2) under the action of an acid, structural formula is the intermediate demethylation of Formula II, obtains pleasure and cuts down for Buddhist nun's impurity.
3. pleasure according to claim 2 is cut down for the preparation method of Buddhist nun's impurity, which is characterized in that the step 1) includes following
Step:
1. happy cut down is mixed in Buddhist nun, the first organic solvent and Pd/C catalyst addition reaction flask；
2. being continually fed into hydrogen into reaction flask, make the reaction that dechlorination occurs in reaction flask, until happy cut down all disappears for Buddhist nun；
3. 2. reaction solution that step is obtained filters, and evaporating solvent under reduced pressure, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, the intermediate that structural formula is Formula II is obtained.
4. pleasure according to claim 3 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: the step 1. in, pleasure cut down
It is 1:0.05~0.20 for the addition mass ratio of Buddhist nun and Pd/C catalyst.
5. pleasure according to claim 3 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: first organic solvent is
One or more of methanol, ethyl alcohol, tetrahydrofuran, acetonitrile, N,N-dimethylformamide；The additional amount of first organic solvent is
Every gram of pleasure, which is cut down, is added the first solvent of 5~50mL for Buddhist nun.
6. pleasure according to claim 3 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: the step 2. in, reaction
Temperature is 10~50 DEG C.
7. pleasure according to claim 2 is cut down for the preparation method of Buddhist nun's impurity, which is characterized in that the step 2) includes following
Step:
1. structural formula is that the intermediate of Formula II and the second solvent are added in reaction flask, add under lasting stirring condition into reaction flask
Enter acid；
2. reaction flask is heated up to 0~100 DEG C, make the liquid reactions in reaction flask, until structural formula is complete for the intermediate of Formula II
It totally disappeared mistake；
3. 2. reaction solution that step is obtained filters or extraction, crude product is obtained；
4. 3. crude product that step is obtained carries out column chromatographic purifying, obtains pleasure and cut down for Buddhist nun's impurity.
8. pleasure according to claim 7 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: second solvent is 1,2-
One or more of dichloroethanes, methylene chloride, chloroform, toluene, acetonitrile, methanol and ethyl alcohol；The addition of second solvent
Amount is that the second solvent of 5~20mL is added in the intermediate that every gram of structural formula is Formula II.
9. pleasure according to claim 7 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: it is described acid be Boron tribromide,
One or more of hydrochloric acid, hydrobromic acid, trifluoroacetic acid, alchlor and acetic acid；The structural formula of the addition is in Formula II
The molar ratio of mesosome and acid is 1:1~10.
10. pleasure according to claim 7 is cut down for the preparation method of Buddhist nun's impurity, it is characterised in that: the reaction of the step 2.
Temperature is 10~80 DEG C.
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