CN110845406A - Preparation method of quinoline compound - Google Patents
Preparation method of quinoline compound Download PDFInfo
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- CN110845406A CN110845406A CN201911226705.4A CN201911226705A CN110845406A CN 110845406 A CN110845406 A CN 110845406A CN 201911226705 A CN201911226705 A CN 201911226705A CN 110845406 A CN110845406 A CN 110845406A
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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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a preparation method of a quinoline compound, wherein the quinoline compound has a structure shown in a formula (I), and the preparation method comprises the following steps: providing a compound having a structure represented by formula (I-1); reacting a compound with a structure shown in a formula (I-1) with 3, 4-difluoro-nitrobenzene to prepare a quinoline compound with a structure shown in the formula (I);
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a preparation method of quinoline compounds.
Background
The treatment of tumors has been a worldwide problem, with malignant tumors becoming the first cause of death. Drug treatment is an important place in triple therapy of malignant tumors. From the current overall trend, the tumor killing capacity of targeted drug therapy and immunotherapy is continuously expanding, and in the future, the targeted drug therapy and immunotherapy will become the middle strength of the anti-tumor battleline. The targeted drug can be used for targeting tumor local parts through tumor-related targets under the condition of minimizing the damage to human cells, can accurately track the targets and attack the targets, and can block the signal conduction of tumor cells or related cells so as to inhibit the growth and proliferation of tumors.
The substituted quinoline compound is proved to have protein tyrosine kinase inhibitory activity, can inhibit receptor signal responses of VEGF, HGF or Axl and the like, and simultaneously acts on a plurality of targets, thereby generating synergistic effect, having lower toxic and side effect and reducing the drug resistance of diseases, achieving better treatment effect on high-value-added diseases, and being widely used for preparing targeted drugs. In particular, 7-oxyquinoline derivatives such as 4- (2-fluoro-4-nitrophenyl) -7-hydroxyquinoline are important components of tyrosine kinase inhibitor antitumor drugs such as Nigatinib tosylate, cabozantinib malate, and Anlotinib hydrochloride. However, the traditional method for synthesizing 4- (2-fluoro-4-nitrophenyl) -7-hydroxyquinoline has the disadvantages of more complicated steps, high process cost, and low production safety because phosphorus oxychloride is required to be used in the reaction step.
Disclosure of Invention
Based on this, there is a need for a method for preparing quinoline compounds with simple steps and without using phosphorus oxychloride.
A preparation method of a quinoline compound, wherein the quinoline compound has a structure shown in a formula (I), and the preparation method comprises the following steps:
providing a compound having a structure represented by formula (I-1);
reacting a compound with a structure shown in a formula (I-1) with 3, 4-difluoro-nitrobenzene to prepare a quinoline compound with a structure shown in the formula (I);
wherein M represents a hydroxyl protecting group.
In one embodiment, M is benzyl.
In one embodiment, the step of reacting a compound having a structure represented by formula (I-1) with 3, 4-difluoro-nitrobenzene comprises the steps of:
reacting a compound with a structure shown in a formula (I-1) with 3, 4-difluoro-nitrobenzene under the action of alkali and a solvent at the temperature of 30-110 ℃, and separating after the reaction is finished to prepare the quinoline compound with the structure shown in the formula (I).
In one embodiment, the step of separating after the reaction is completed comprises the steps of:
cooling to below 30 deg.C after reaction, adding water, separating out solid, filtering to obtain solid, adding ethanol, stirring at 40-70 deg.C, slowly cooling to below 30 deg.C, filtering to obtain solid, and drying.
In one embodiment, the solvent is selected from: one or more of butanone, acetonitrile, N-Dimethylformamide (DMF), Dimethylacetamide (DMAC), and dioxane; and/or
The base is selected from: one or more of N, N-Diisopropylethylamine (DIPEA), Triethylamine (TEA), pyridine, heteronitrogen bicyclic ring (DBU), potassium carbonate, sodium carbonate and cesium carbonate.
In one embodiment, the compound with the structure shown in the formula (I-1) is prepared by the following steps:
providing a compound having a structure represented by formula (I-2);
carrying out a ring closure reaction on the compound with the structure shown in the formula (I-2) to prepare the compound with the structure shown in the formula (I-1);
wherein R is1And R2Each independently is C1-3An alkyl group.
In one embodiment, the step of subjecting the compound having the structure represented by formula (I-2) to a ring closure reaction comprises the steps of:
mixing o-dichlorobenzene and a compound with a structure shown in a formula (I-2), heating the mixture in an organic solvent to 160-200 ℃ for reaction, cooling the mixture to 0-30 ℃ after the reaction is finished, separating out solids, filtering, collecting the solids, washing and drying the solids.
In one embodiment, the compound with the structure shown in the formula (I-2) is prepared by the following steps:
reacting a compound having a structure represented by the formula (I-3), a compound having a structure represented by the formula (I-4) and a compound having a structure represented by the formula (I-5) to obtain a compound having a structure represented by the formula (I-2);
wherein R is3、R4And R5Each independently is C1-3An alkyl group.
In one embodiment, the step of reacting the compound of the structure represented by the formula (I-3), the compound of the structure represented by the formula (I-4), and the compound of the structure represented by the formula (I-5) comprises the steps of:
mixing a compound with a structure shown in a formula (I-3), a compound with a structure shown in a formula (I-4), a compound with a structure shown in a formula (I-5) and a solvent, carrying out reflux reaction, cooling to-5 ℃ after complete reaction, stirring, separating out solids, filtering, collecting the solids, washing and drying.
In one embodiment, R1And R2Are each methyl, R3、R4And R5Are all ethyl
Researchers of the invention innovatively adopt 3, 4-difluoro-nitrobenzene and the compound with the structure shown in the formula (I-1) to carry out substitution reaction through a large amount of researches, and because both nitro and fluorine atoms are stronger electron-withdrawing groups, the nitro and the fluorine atoms can directly react with hydroxyl in the compound with the structure shown in the formula (I-1), and reagents such as phosphorus oxychloride and the like are not needed to convert the hydroxyl in the compound with the structure shown in the formula (I-1), so that the reaction steps are shortened on one hand, and the difficulty of industrial production is reduced; on the other hand, the production safety is improved, the method is more beneficial to large-scale industrial production, and reactants in the steps are cheap and easy to obtain, the cost is lower, and the method is suitable for industrial production.
In addition, the invention creatively selects the 3, 4-difluoro-nitrobenzene of which the meta position and the para position both contain fluorine atoms, and the existence of two fluorine atoms can improve the electrophilicity of the 3, 4-difluoro-nitrobenzene and improve the yield, and the strong electron-withdrawing action of the nitro group enables the para position to be easily subjected to substitution reaction, so that a para position substitution product can be obtained with high yield, the generation of byproducts is reduced, and the post-treatment difficulty is reduced.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The invention provides a preparation method of a quinoline compound, which comprises the following steps:
s101, providing a compound with a structure shown in a formula (I-1);
wherein M represents a hydroxyl protecting group, preferably M is benzyl.
The compound having the structure represented by the formula (I-1) can be synthesized by a conventional method, and is not particularly limited, and is preferably prepared by the following method:
s1011: reacting a compound having a structure represented by the formula (I-3), a compound having a structure represented by the formula (I-4) and a compound having a structure represented by the formula (I-5) to obtain a compound having a structure represented by the formula (I-2);
wherein R is1And R2Each independently is C1-3An alkyl group; r3、R4And R5Each independently is C1-3An alkyl group.
In one embodiment, R1And R2Are both methyl; r3、R4And R5Are all ethyl groups.
Further, step S1011 includes the steps of: mixing a compound with a structure shown in a formula (I-3), a compound with a structure shown in a formula (I-4), a compound with a structure shown in a formula (I-5) and a solvent, carrying out reflux reaction, cooling to-5 ℃ after complete reaction, stirring, separating out solids, filtering, washing and drying.
Wherein the solvent includes, but is not limited to, ethanol.
Preferably, absolute ethyl alcohol is used as a solvent, so that side reactions are reduced, the post-treatment difficulty is reduced, and the yield is improved.
It is understood that when it is desired to use a reactant containing a protecting group, which also includes a step of protecting group, the existing protecting group-applying method can be used, and is not particularly limited herein, and should be understood to be within the scope of the present invention, for example: the compound with the structure shown in the formula (I-3) can be prepared by reacting 3-hydroxyaniline with benzyl bromide and the like. After the protecting group reaction is carried out, the subsequent reaction can be directly carried out without separating the prepared product containing the protecting group, and the subsequent step can also be carried out after the prepared product containing the protecting group is separated, which is understood to be in the protection scope of the invention. When it is desired to use a product without a protecting group, a step of removing the protecting group is also included, and the removal can be performed by a conventional method, which is not particularly limited herein, and is understood to be within the scope of the present invention.
The method has the advantages of high yield, easy product separation, no need of complicated post-treatment methods such as column chromatography and the like, cooling after the reaction is finished, separating out the product, and then carrying out simple pulping treatment. The production efficiency is greatly improved, the production cost is reduced, the industrialization is facilitated, and the three raw materials in the step S1011 all belong to cheap and easily available raw materials, so that the production cost can be further reduced.
S1012: carrying out a ring closure reaction on the compound with the structure shown in the formula (I-2) to prepare the compound with the structure shown in the formula (I-1);
it is understood that when the compound having the structure represented by formula (I-2) can be obtained by the conventional method, step S1011 can be omitted. It is preferable to synthesize a compound having a structure represented by formula (I-2) in step S1011 to reduce the cost.
Further, S1012 includes the steps of: mixing o-dichlorobenzene and a compound with a structure shown in a formula (I-2), heating to 160-200 ℃, cooling to 0-30 ℃ after the reaction is finished, separating out solids, filtering, washing and drying.
Further, S1012 includes the steps of: mixing o-dichlorobenzene and a compound with a structure shown as a formula (I-2), heating to 180 ℃, reacting for 6-8h, cooling to 15-25 ℃, stirring for 1-3 h, separating out solids, filtering, pulping by adopting Dichloromethane (DCM), stirring for 1-3 h at 20-30 ℃, filtering, and drying.
And step S1012 has simple reaction conditions and simple post-treatment, does not need complicated operations such as column chromatography and the like, and can further reduce the production difficulty and the production cost.
S102, reacting the compound with the structure shown in the formula (I-1) with 3, 4-difluoro-nitrobenzene to obtain the quinoline compound with the structure shown in the formula (I);
the applicant innovatively adopts 3, 4-difluoro-nitrobenzene and the compound with the structure shown in the formula (I-1) to carry out substitution reaction through a great deal of research, and because both nitro and fluorine atoms are strong electron-withdrawing groups, the nitro and the fluorine atoms can directly react with hydroxyl in the compound with the structure shown in the formula (I-1), and reagents such as phosphorus oxychloride and the like are not required to be adopted to convert the hydroxyl in the compound with the structure shown in the formula (I-1), so that the reaction steps are shortened on one hand, and the difficulty of industrial production is reduced; on the other hand, the production safety is improved, the method is more beneficial to large-scale industrial production, and reactants in the steps are cheap and easy to obtain, so that the method is suitable for industrial production.
In addition, the applicant creatively selects a reagent containing fluorine atoms at both the meta position and the para position of the nitro group, the existence of the two fluorine atoms can improve the electrophilicity of the 3, 4-difluoro-nitrobenzene and improve the yield, and the strong electron-withdrawing action of the nitro group enables the para position to be easily subjected to substitution reaction, so that a para position substitution product can be obtained at high yield, the generation of byproducts is reduced, and the post-treatment difficulty is reduced.
Further, step S102 includes the steps of:
mixing a compound with a structure shown in a formula (I-1), a compound with a structure shown in a formula (I-2), alkali and a solvent, reacting, separating and filtering after the reaction is finished, and obtaining the quinoline compound with the structure shown in the formula (I).
Further, step S102 includes the steps of:
mixing a compound with a structure shown in a formula (I-1), a compound with a structure shown in a formula (I-2), alkali and a solvent, reacting, cooling to below 30 ℃ (preferably below 20 ℃) after the reaction is finished, adding water, separating out solids, filtering, adding ethanol into the solids, stirring at 40-70 ℃, slowly cooling to below 30 ℃, filtering, and drying to obtain the quinoline compound with the structure shown in the formula (I).
Among them, preferred solvents are polar aprotic solvents including, but not limited to, one or more of toluene, butanone, acetonitrile, N-Dimethylformamide (DMF), Dimethylacetamide (DMAC), and dioxane. The base may be an organic base and/or an inorganic base, specifically including but not limited to one or more of N, N-Diisopropylethylamine (DIPEA), Triethylamine (TEA), pyridine, azabicyclo (DBU), potassium carbonate, sodium carbonate, and cesium carbonate; preferably, DIPEA is used, and applicants have found that the use of DIPEA in the reaction of step S102 results in less side reactions, easy purification, and high product purity.
Further, the reaction temperature is preferably 30 to 110 ℃, more preferably 65 to 95 ℃ to improve the yield.
Further, the molar ratio of the compound having the structure represented by the formula (I-1) to the compound having the structure represented by the formula (I-2) is 1/1.02 to 1/1.50; the molar ratio of the compound having the structure represented by the formula (I-1) to the base is 1/1.1 to 1/1.50.
Further, the volume of water added in the step of the post-treatment (i.e., in the separation step after completion of the reaction) is (1 to 4 times, preferably 2.5 to 3.5 times the volume of the solvent.
The present invention will be described below with reference to specific examples.
Example 1
Synthesis of Compound 1
To a 2L three-necked flask were added anhydrous ethanol (300mL), 3-benzyloxyaniline (300g), triethyl orthoformate (245g) and isopropylidene malonate (261g) in this order, and the mixture was stirred and heated to reflux for 3 hours, followed by TLC detection to complete the reaction. Cooling to 0 deg.C, stirring for 0.5h, filtering, and washing the solid with appropriate amount of cold ethanol once. The resulting solid was slurried with anhydrous ethanol (225mL) at 0 deg.C for 2 hours with stirring, filtered, the solid washed once with an appropriate amount of cold ethanol and air dried at 50 deg.C to give Compound 1(460.5g, 86.5%).
MS(ESI,neg.ion)m/z：352.3[M-1]；
1H NMR(400MHz,DMSO-d6):δ1.71(s,6H),5.16(s,2H),6.91(dd,J＝2.0Hz,J＝8.0Hz,1H),7.13(dd,J＝1.6Hz,J＝8.0Hz,1H),7.32-7.36(m,3H),7.39-7.43(m,2H),7.48(d,J＝7.2Hz,1H),8.63(d,J＝14.4Hz,1H),11.23(d,J＝14.4Hz,1H).
Synthesis of Compound 2
To a 1L reaction flask were added o-dichlorobenzene (500mL) and compound 1(50.0g) in that order, and the reaction was checked by TLC while stirring and raising the temperature to 180 ℃ for 5 hours. After the reaction is finished, slowly cooling to 20 ℃, stirring for 2h, and filtering to obtain a solid. The resulting solid was slurried with DCM (100mL) at 20 deg.C-30 deg.C with stirring for 2 hours, filtered, and dried to give Compound 2(18.3g, 48%).
MS(ESI,pos.ion)m/z：252.2[M+1]；
1H NMR(400MHz,DMSO-d6):δ5.23(s,2H),5.98(d,J＝7.2Hz,1H),7.02(t,2H),7.41(t,1H),7.45(t,J＝6.8Hz,J＝7.6Hz,2H),7.52(d,J＝7.6Hz,2H),7.84(t,J＝6.4Hz,J＝6.0Hz,1H),8.03(d,J＝9.2Hz,1H),11.60(s,1H).
Synthesis of Compound 3
DMF (140mL), 3, 4-difluoro-nitrobenzene (90.0g), compound 2(140.0g) and DIPEA (88.0g) were added to a 1L reaction flask in this order, stirred and warmed to 85 ℃ and reacted overnight before starting the reaction by TLC. After the reaction, the temperature is reduced to below 20 ℃, water (420mL) is added under the temperature controlled to be below 30 ℃, the mixture is filtered, ethanol (140mL) is added into the solid, the mixture is stirred for 1h at the temperature of 60 ℃, the mixture is slowly cooled to the room temperature and stirred for 30min, and the mixture is filtered and dried by blowing air at the temperature of 60 ℃ to obtain the compound 3(190.0g, 95%).
MS(ESI,pos.ion)m/z：391.1[M+1]；
1H NMR(400MHz,DMSO-d6):δ5.33(s,2H),6.79(d,J＝4.8Hz,1H),7.37(t,1H),7.39-7.44(m,3H),7.52-7.57(m,3H),7.64(t,J＝8.4Hz,J＝8.8Hz,1H),8.16-8.21(m,2H),8.46(dd,J＝2.8Hz,J＝10.4Hz,1H),8.71(d,J＝4.8Hz,1H).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A preparation method of a quinoline compound, which is characterized by having a structure shown in a formula (I) and comprises the following steps:
providing a compound having a structure represented by formula (I-1);
reacting a compound with a structure shown in a formula (I-1) with 3, 4-difluoro-nitrobenzene to prepare a quinoline compound with a structure shown in the formula (I);
wherein M represents a hydroxyl protecting group.
2. The process according to claim 1, wherein M is benzyl.
3. The method according to claim 1, wherein the step of reacting the compound having the structure represented by formula (I-1) with 3, 4-difluoro-nitrobenzene comprises the steps of:
reacting a compound with a structure shown in a formula (I-1) with 3, 4-difluoro-nitrobenzene under the action of alkali and a solvent at the temperature of 30-110 ℃, and separating after the reaction is finished to obtain the quinoline compound with the structure shown in the formula (I).
4. The method of claim 3, wherein the step of separating after completion of the reaction comprises the steps of:
cooling to below 30 deg.C after reaction, adding water to precipitate solid, filtering to obtain solid, adding ethanol, stirring at 40-70 deg.C, slowly cooling to below 30 deg.C, filtering to obtain solid, and drying.
5. The method according to claim 3, wherein the solvent is selected from the group consisting of: one or more of butanone, acetonitrile, N-dimethylformamide, dimethylacetamide, and dioxane; and/or
The base is selected from: one or more of N, N-diisopropylethylamine, triethylamine, pyridine, azabicyclo, potassium carbonate, sodium carbonate and cesium carbonate.
6. The method according to any one of claims 1 to 5, wherein the compound having the structure represented by formula (I-1) is prepared by the following steps:
providing a compound having a structure represented by formula (I-2);
carrying out a ring closure reaction on the compound with the structure shown in the formula (I-2) to prepare the compound with the structure shown in the formula (I-1);
wherein R is1And R2Each independently is C1-3An alkyl group.
7. The method according to claim 6, wherein the step of subjecting the compound of the structure represented by the formula (I-2) to a ring closure reaction comprises the steps of:
mixing o-dichlorobenzene and a compound with a structure shown in a formula (I-2), heating the mixture in an organic solvent to 160-200 ℃ for reaction, cooling the mixture to 0-30 ℃ after the reaction is finished, separating out solids, collecting the solids, washing and drying the solids.
8. The method according to claim 6, wherein the compound having the structure represented by formula (I-2) is prepared by the following steps:
reacting a compound having a structure represented by the formula (I-3), a compound having a structure represented by the formula (I-4) and a compound having a structure represented by the formula (I-5) to obtain a compound having a structure represented by the formula (I-2);
wherein R is3、R4And R5Each independently is C1-3An alkyl group.
9. The method according to claim 8, wherein the step of reacting the compound of the structure represented by the formula (I-3), the compound of the structure represented by the formula (I-4), and the compound of the structure represented by the formula (I-5) comprises the steps of:
mixing a compound with a structure shown in a formula (I-3), a compound with a structure shown in a formula (I-4), a compound with a structure shown in a formula (I-5) and a solvent, carrying out reflux reaction, cooling to-5 ℃ after complete reaction, stirring, separating out solids, filtering, collecting the solids, washing and drying.
10. The method of claim 9, wherein R is1And R2Are each methyl, R3、R4And R5Are all ethyl groups.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008035209A2 (en) * | 2006-05-30 | 2008-03-27 | Methylgene Inc. | Inhibitors of protein tyrosine kinase activity |
| WO2012118632A1 (en) * | 2011-02-28 | 2012-09-07 | Ning Xi | Substituted quinoline compounds and methods of use |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
| CN109456267A (en) * | 2018-12-28 | 2019-03-12 | 南京天越星生物技术有限公司 | A method of synthesis pleasure is cut down for Buddhist nun |
| WO2019148044A1 (en) * | 2018-01-26 | 2019-08-01 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008035209A2 (en) * | 2006-05-30 | 2008-03-27 | Methylgene Inc. | Inhibitors of protein tyrosine kinase activity |
| WO2012118632A1 (en) * | 2011-02-28 | 2012-09-07 | Ning Xi | Substituted quinoline compounds and methods of use |
| CN102675282A (en) * | 2011-03-15 | 2012-09-19 | 广东东阳光药业有限公司 | Substitutive quinoline compound and application method and uses thereof |
| WO2019148044A1 (en) * | 2018-01-26 | 2019-08-01 | Exelixis, Inc. | Compounds for the treatment of kinase-dependent disorders |
| CN109456267A (en) * | 2018-12-28 | 2019-03-12 | 南京天越星生物技术有限公司 | A method of synthesis pleasure is cut down for Buddhist nun |
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