CN103923073A - Puerarin derivative preparation method - Google Patents

Puerarin derivative preparation method Download PDF

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Publication number
CN103923073A
CN103923073A CN201410152287.XA CN201410152287A CN103923073A CN 103923073 A CN103923073 A CN 103923073A CN 201410152287 A CN201410152287 A CN 201410152287A CN 103923073 A CN103923073 A CN 103923073A
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China
Prior art keywords
puerarin
hydrochloric acid
preparation
reaction
derivate
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CN201410152287.XA
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CN103923073B (en
Inventor
梁剑平
陶蕾
尚若锋
赵凤舞
王学红
贾忠
郝宝成
刘宇
郭文柱
郭志廷
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SHANDONG COHESION ANIMAL PHARMACEUTICAL Co.,Ltd.
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Lanzhou Institute of Animal Husbandry and Veterinary Medicine CAAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention discloses a puerarin derivative preparation method. Puerarin derivative has the structural formula as shown in the specification, and the puerarin derivative is obtained by that puerarin reacts with CH2(R)2, wherein R is a tertiary amine gene. The puerarin derivative preparation method is characterized in that reaction is carried out under hydrochloric acid catalysis. Compared with the prior art, the puerarin derivative preparation method is characterized in that the yield of a puerarin derivative product can be obviously improved after the class of reaction adopts hydrochloric acid catalysis.

Description

The preparation method of puerarin derivate
Technical field
The invention belongs to the synthetic field of medicine, be specifically related to the preparation method of puerarin derivatives.
Background technology
Puerarin is a kind of flavonoid glycoside extracting in the dry root by legume pueraria lobata or sweet kudzu, chemical name is 4 ', 7-dihydroxyl-8-D-glucone isoflavone, as improve must the cerebrovascular new drug of circulation, puerarin toxicity is little, peace closes that scope is wide, good effect and have clinical value.But due to its isoflavones structure, water-soluble and be fat-solublely all on duty mutually, bioavailability is bad, for this reason, puerarin is carried out to structure of modification, has great importance to improve its performance.Guo Yansheng discloses by puerarin and R in the second section (13-34 page) of " extraction, separation and the structure of modification of kudzu vine root puerarin " (Gansu Agriculture University 2004) paper 1r 2nCH 2nR 1r 2in pyridine solvent, react, at 3 ' or 5 ' different tertiary amine group (CH of upper introducing of puerarin 2nR 1r 2), thereby obtain the puerarin derivate of class 3 ' or 5 ' bit strip base groups, but the deficiency of its synthetic method is that the yield of each reaction product is very low.
Summary of the invention
The object of the invention is above-mentioned synthetic method to improve, a kind of preparation method of puerarin derivate is provided.
It is as follows that the present invention realizes the technical scheme that above-mentioned purpose adopts:
The preparation method of puerarin derivate, the structural formula of described puerarin derivate is:
, or be
, described puerarin derivate is by puerarin and CH 2(R) 2reaction obtains, and wherein, R is tertiary amine group, and its feature is, described puerarin and CH 2(R) 2reaction under hydrochloric acid catalysis, carry out.
Further, described tertiary amine group is-N (R 1) 2or cyclammonium base, wherein, R 1for alkyl.
Further, the alkyl that described alkyl is C1-C4.
Further, described cyclammonium base is morpholine group, hexahydropyridine group or Pyrrolidine group.
Further, by the amount of HCl in hydrochloric acid, the add-on of described hydrochloric acid is 0.4～2.5 times of puerarin weight.
Compared with prior art, the present invention finds that such reaction adopts after hydrochloric acid catalysis, can significantly improve the yield of product.
Brief description of the drawings
Fig. 1 is the infrared spectrogram of 3 '-methylene radical-dimethylamine-puerarin described in embodiment 1.
Fig. 2 is the hydrogen nuclear magnetic resonance spectrogram of 3 '-methylene radical-dimethylamine-puerarin described in embodiment 1.
Fig. 3 is the infrared spectrogram of 3 ', 5 '-methylene radical-diethylamine-puerarin described in embodiment 2.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of 3 ', 5 '-methylene radical-diethylamine-puerarin described in embodiment 2.
Fig. 5 is the infrared spectrogram of 3 '-methylene radical-morpholine-puerarin described in embodiment 3.
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of 3 '-methylene radical-morpholine-puerarin described in embodiment 3.
Fig. 7 is the infrared spectrogram of 3 '-methylene radical-hexahydropyridine-puerarin described in embodiment 4.
Fig. 8 is the hydrogen nuclear magnetic resonance spectrogram of 3 '-methylene radical-hexahydropyridine-puerarin described in embodiment 4.
Fig. 9 is the infrared spectrogram of 3 '-methylene radical-Pyrrolidine-puerarin described in embodiment 5.
Figure 10 is the hydrogen nuclear magnetic resonance spectrogram of 3 '-methylene radical-Pyrrolidine-puerarin described in embodiment 5.
Embodiment
Below in conjunction with embodiment, the present invention is described in further details.
Embodiment 1
1) two-(dimethylamine) methane is synthetic
Under ice-water bath is cooling, add the formalin of 15ml 37wt% in reaction flask, under stirring, drip the aqueous solution of 50ml 33wt% Dimethylammonium chloride with dropping funnel, after dropwising, stirring at room temperature 30min, then adds solid NaOH to form two-phase to solution, separating funnel is divided into two-layer, dry with solid NaOH, place and filter, air distillation, collect 83 DEG C of cuts , (CH 3) 2nCH 2n (CH 3) 2.
2) synthetic (I) of 3 '-methylene radical-dimethylamine-puerarin
Accurately take 0.146g puerarin and be placed in 100mL three-necked bottle, add 10mL anhydrous pyridine to make it to dissolve, with 0.175g pair of dropping funnel dropping-(dimethylamine) methane and 0.8mL concentrated hydrochloric acid (37wt%, about 1.19g/cm of density 3), 60 DEG C of reflux, TLC follows the tracks of reaction, reacts 4 hours, and stopped reaction, removes solvent under reduced pressure, with mixed solvent (CH 3cl-CH 3oH, 4:1, V/V) carry out recrystallization, obtain dark red solid crystallization (95.3mg, yield 65%), product structure formula: .
Under other condition same case, puerarin and two-(dimethylamine) methane react without hydrochloric acid catalysis time, product yield only has 45% left and right.
Embodiment 2
1) two-(diethylamine) methane is synthetic
In three-necked bottle, add the formalin 76mL of 40wt% under ice-water bath is cooling, with dropping funnel dropping 111g diethylamine, temperature maintains 20-25 DEG C, after 1h dropwises, stirring at room temperature 4h, then adds solid NaOH to form two-phase to solution, separating funnel is divided into two-layer, with anhydrous sodium sulfate drying, place and filter, air distillation, collect 158-160 DEG C of cut .
2) synthetic (II) of 3 ', 5 '-methylene radical-diethylamine-puerarin
Accurately take 0.832g puerarin in 100mL three-necked bottle, add 10mL anhydrous pyridine to make it to dissolve, with 0.175g pair-(diethylamine) methane of dropping funnel dropping and a 0.8mL concentrated hydrochloric acid (37wt%), 80 DEG C of reflux, TLC follows the tracks of reaction, reaction 6h, stopped reaction, remove solvent under reduced pressure, (CH in mixed solvent 3cl-CH 3oH-H 2o, 95:40:1, V/V) recrystallization, obtain dark red solid crystallization (557.4mg, yield 67%), product structure formula: .
Under other condition same case, puerarin and two-(diethylamine) methane react without hydrochloric acid catalysis time, product yield only has 25% left and right.
Embodiment 3
1) two-(morpholine) methane is synthetic
In three-necked bottle, add the morpholine of 36g, under ice-water bath is cooling, the formalin that drips 17g 40wt% with dropping funnel, temperature maintains 40-50 DEG C, after 1h dropwises, stirring at room temperature 2h, be placed to solution and form two-phase, separating funnel is divided into upper strata, with anhydrous sodium sulfate drying, place and filter, air distillation, collects 90-92 DEG C of cut, reacts as follows:
。
2) synthetic (III) of 3 '-methylene radical-morpholine-puerarin
Accurately take 0.832g puerarin in 100mL three-necked bottle, add 20mL anhydrous pyridine to make it to dissolve, with 0.39g pair of dropping funnel dropping-(morpholine) methane and 0.8mL concentrated hydrochloric acid (37wt%), 100 DEG C of reflux, TLC follows the tracks of reaction, reaction 8h, stopped reaction, remove solvent under reduced pressure, (CH in mixed solvent 3cl-CH 3oH-H 2o, 95:30:4, V/V) recrystallization, obtain dark red solid crystallization 537.3 mg(yields 65%), product structure formula:
。
Under other condition same case, puerarin and two-(morpholine) methane react without hydrochloric acid catalysis time, product yield only has 15% left and right.
Embodiment 4
1) two-(hexahydropyridine) methane is synthetic
In three-necked bottle, add the formalin of 10mL 40wt%, under ice-water bath is cooling, with dropping funnel dropping 23mL hexahydropyridine, temperature maintains 4 DEG C, after 1h dropwises, stirring at room temperature 2h, be placed to solution and form two-phase, separating funnel is divided into upper strata, dry with sodium hydroxide, place and filter, air distillation, collects 85-90 DEG C of cut, reacts as follows:
。
2) synthetic (IV) of 3 '-methylene radical-hexahydropyridine-puerarin
Accurately take 0.416g puerarin in 100mL three-necked bottle, add 10mL anhydrous pyridine to make it to dissolve, with 0.402g pair of dropping funnel dropping-(hexahydropyridine) methane and 0.8mL concentrated hydrochloric acid (37wt%), 80 DEG C of reflux, TLC follows the tracks of reaction, reaction 8h, stopped reaction, remove solvent under reduced pressure, (CH in mixed solvent 3cl-CH 3oH, 2:1, V/V) recrystallization, obtain yellow solid crystallization 228.3mg(yield 56%), product structure formula:
。
Under other condition same case, puerarin and two-(hexahydropyridine) methane react without hydrochloric acid catalysis time, product yield only has 26% left and right.
Embodiment 5
1) two-(Pyrrolidine) methane is synthetic
In three-necked bottle, add the formalin 10mL of 40wt%, under ice-water bath is cooling, with dropping funnel dropping 17mL Pyrrolidine, temperature maintains 40-50 DEG C, after 1h dropwises, stirring at room temperature 2h, be placed to solution and form two-phase, separating funnel is divided into upper strata, with anhydrous sodium sulfate drying, place and filter, air distillation, collects 100-105 DEG C of cut, reacts as follows:
。
2) 3 '-methylene radical-Pyrrolidine-puerarin is synthetic
Accurately take 0.832g puerarin in 100mL three-necked bottle, add 20mL anhydrous pyridine to make it to dissolve, with 0.308g pair-(Pyrrolidine) methane of dropping funnel dropping and a 0.8mL concentrated hydrochloric acid (37wt%), 120 DEG C of reflux, TLC follows the tracks of reaction, reaction 5h, stopped reaction, remove solvent under reduced pressure, (CH in mixed solvent 3cl-CH 3oH-H 2o, 95:30:3, V/V) recrystallization, obtain dark red solid crystallization 581mg(yield 70%), product structure formula:
?。
Under other condition same case, puerarin and two-(Pyrrolidine) methane react without hydrochloric acid catalysis time, product yield only has 10% left and right.

Claims (5)

1. the preparation method of puerarin derivate, the structural formula of described puerarin derivate is:
, or be
, described puerarin derivate is by puerarin and CH 2(R) 2reaction obtains, and wherein, R is tertiary amine group, it is characterized in that, described puerarin and CH 2(R) 2reaction be to carry out under hydrochloric acid catalysis.
2. the preparation method of puerarin derivate according to claim 1, is characterized in that, described tertiary amine group is-N (R 1) 2or cyclammonium base, wherein, R 1for alkyl.
3. the preparation method of puerarin derivate according to claim 1, is characterized in that the alkyl that described alkyl is C1-C4.
4. the preparation method of puerarin derivate according to claim 1, is characterized in that, described cyclammonium base is morpholine group, hexahydropyridine group or Pyrrolidine group.
5. the preparation method of puerarin derivate according to claim 1, is characterized in that, by the amount of HCl in hydrochloric acid, the add-on of described hydrochloric acid is 0.4～2.5 times of puerarin weight.
CN201410152287.XA 2014-04-16 2014-04-16 The preparation method of puerarin derivate Active CN103923073B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484529A (en) * 2018-06-06 2018-09-04 南通江天化学股份有限公司 A kind of synthetic method of N, N '-di-2-ethylhexylphosphine oxide morpholine

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101255119A (en) * 2008-01-07 2008-09-03 沈阳药科大学 Novel tetrahydro curcumin derivatives and salt
CN101591370A (en) * 2008-05-27 2009-12-02 中国农业科学院兰州畜牧与兽药研究所 The synthetic method of puerarin derivatives
RU2384567C2 (en) * 2008-03-03 2010-03-20 ИНСТИТУТ НЕФТЕХИМИИ И КАТАЛИЗА Российской Академии Наук Method of producing 2-[(dimethylamino)methyl]phenol
CN101805332A (en) * 2010-04-30 2010-08-18 西安力邦制药有限公司 Preparation method and application of puerarin derivatives
RU2447076C1 (en) * 2010-12-09 2012-04-10 Закрытое Акционерное Общество "Фарм-Синтез" Method of producing topotecan

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101255119A (en) * 2008-01-07 2008-09-03 沈阳药科大学 Novel tetrahydro curcumin derivatives and salt
RU2384567C2 (en) * 2008-03-03 2010-03-20 ИНСТИТУТ НЕФТЕХИМИИ И КАТАЛИЗА Российской Академии Наук Method of producing 2-[(dimethylamino)methyl]phenol
CN101591370A (en) * 2008-05-27 2009-12-02 中国农业科学院兰州畜牧与兽药研究所 The synthetic method of puerarin derivatives
CN101805332A (en) * 2010-04-30 2010-08-18 西安力邦制药有限公司 Preparation method and application of puerarin derivatives
RU2447076C1 (en) * 2010-12-09 2012-04-10 Закрытое Акционерное Общество "Фарм-Синтез" Method of producing topotecan

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108484529A (en) * 2018-06-06 2018-09-04 南通江天化学股份有限公司 A kind of synthetic method of N, N '-di-2-ethylhexylphosphine oxide morpholine

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Effective date of registration: 20200902

Address after: Qufan village, GuDi sub district office, Hanting District, Weifang City, Shandong Province

Patentee after: SHANDONG COHESION ANIMAL PHARMACEUTICAL Co.,Ltd.

Address before: 730000 Gansu city of Lanzhou province West Lake Qilihe district along the 335 base

Patentee before: LANZHOU INSTITUTE OF HUSBANDRY AND PHARMACEUTICAL SCIENCES OF CAAS