CN103896998A - Method for preparing gastrodin intermediate and method for synthesizing gastrodin - Google Patents
Method for preparing gastrodin intermediate and method for synthesizing gastrodin Download PDFInfo
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Abstract
The invention discloses a method for preparing a gastrodin intermediate compound III. The method comprises the following steps: (1) reducing an initial raw material compound I through hydrogen, and obtaining a compound II; (2) reacting the compound II with an acetylation reagent, and obtaining a crude product of a compound III; and (3) recrystallizing the compound III obtained in the step (2), and obtaining a crude product of the compound III. In addition, the invention also provides a method for synthesizing gastrodin. The compound III prepared by the method provided in the invention is easy to recrystallize and high in purity, and a high-purity gastrodin finished product can be obtained.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to the preparation method of Gastrodin Intermediate, further, also relate to the synthetic method of Gastrodine.
Background technology
Gastrodine is the main active ingredient of orchid rhizoma Gastrodiae (Gastrodia elataBlume), there is the effects such as calm, anticonvulsion, anti-inflammatory and enhancing body immunity, be widely used in clinically the assisting therapy of dizzy, headache (neurasthenia and neurasthenia syndrome, vascular headache, tonus headache, combined external head injuries, migraine etc.) and epilepsy.Its chemical structural formula is as follows:
At present, the Gastrodine bulk drug of clinical application is mainly derived from plant extract and two kinds of methods of chemosynthesis.Due to Gastrodine content in rhizoma Gastrodiae extremely low (approximately 0.1%), therefore adopt plant extraction method to obtain that Gastrodine exists that extraction cost is high, workload is large, high purity sample is difficult to preparation and be unfavorable for the problems such as conservation of resources.Adopt in recent years the method for synthetic to prepare scale and the output expanding day of Gastrodine.Recent domestic discloses the method for many chemosynthesis Gastrodines.
The people such as Zhou Jun are at " chemical journal " 1980; 2 (32): the synthetic method (its committed step is as follows) of having reported Gastrodine in 162-166; this route obtains penta-acetyl glucose with glucose response after with perchloric acid catalysis diacetyl oxide; then bromo, again with p-Hydroxybenzaldehyde condensation, restore and obtain Gastrodine.This route uses POTASSIUM BOROHYDRIDE, red phosphorus, bromine in a large number, not only easy bumping aborning, and do not meet current environmental protection concept, and in addition, the total yield of this route is lower, and production cost is higher.
Wearing is familiar with waits people at " chemical journal " 2004,2 (13): 53-55, the people's such as Zhou Jun operational path to be had made some improvements, and mainly comprises two step committed steps, the first step: acetyl glucose bromide glycoside compound intermediate synthetic; Second step: the condensation reaction of bromo acetyl sugar compounds and phenoloid, generates the phenol glycoside compounds that ethanoyl is protected.Improve although synthetic method has been carried out to some, and red phosphorus and bromine are replaced with phosphorus pentabromide, but still need polystep reaction, and by product is many, reaction specificity is poor, is unsuitable for suitability for industrialized production.
Chinese patent application CN102516329A discloses a kind of synthetic method of Gastrodine, taking glucose as starting raw material, pass into hydrogen bromide and carry out bromo, rear and p-Hydroxybenzaldehyde condensation, can obtain Gastrodine (its step is as follows) through aldehyde radical reduction, deprotection, recrystallization; Although this highway route design is succinct, reaction conditions is relatively gentle, because the product after shortening is difficult for crystallization, through the method for the treatment of different things alike deprotection again, in the Gastrodine obtaining, its related substances is too high, and quality product is difficult to reach standards of pharmacopoeia regulation.
Summary of the invention
The invention provides a kind of high purity Gastrodine key intermediate is the synthetic method of compound III, further, by this intermediate deprotection, can obtain highly purified Gastrodine.
The object of the present invention is to provide a kind of Gastrodin Intermediate is the preparation method of compound III.
Another object of the present invention is to provide and comprises that above-mentioned this intermediate preparation method's prepares Gastrodine novel method.
Specifically, the invention provides the preparation method that a kind of Gastrodine key intermediate is compound III, formed by following steps:
(1), by starting material compound I with hydrogen reducing, obtain Compound I I;
(2), Compound I I reacts with acetylation reagent, obtains compound III crude product;
(3), by step (2) gained compound III crude product recrystallization, obtain the sterling of compound III.
In present specification, in Compound I, Compound I I and compound III, Ac represents ethanoyl.
Be in the preparation method of compound III at Gastrodine key intermediate provided by the invention, wherein, hydrogen reducing described in step (1), refers under thunder Buddhist nun (Rany)-Ni, ruthenium-carbon or Pd-C catalytic condition and carries out.The reduction of step (1) is carried out under C1-C4 alkanol exists, and preferably, in methyl alcohol or alcohol solvent, carries out.
Be in the preparation method of compound III at Gastrodine key intermediate provided by the invention, wherein, acetylation reagent described in step (2), is selected from diacetyl oxide or Acetyl Chloride 98Min..
Be in the preparation method of compound III at Gastrodine key intermediate provided by the invention, wherein, reaction described in step (2) is to carry out under the condition of organic bases or mineral alkali existence, here, described organic bases is selected from triethylamine, N, N-diisopropylethylamine or pyridine, be preferably triethylamine; Described mineral alkali is selected from alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate, is preferably sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, more preferably sodium carbonate, salt of wormwood or sodium bicarbonate.
Be in the preparation method of compound III at Gastrodine key intermediate provided by the invention, wherein, described in step (3), recrystallization carries out in C1-C4 alkanol solvent.Described recrystallization can carry out in a kind of C1-C4 alkanol solvent, also can in the mixed solvent of two or more C1-C4 alkanols, carry out.Preferred described recrystallization carries out in methyl alcohol and/or ethanol, more preferably in methyl alcohol, carries out.
In a preferred embodiment, the invention provides the preparation method that a kind of Gastrodine key intermediate is compound III, formed by following steps:
(1), by starting material compound I with hydrogen reducing, obtain Compound I I;
(2), Compound I I reacts with acetylation reagent, obtains compound III crude product;
(3), by step (2) gained compound III recrystallization, obtain the sterling of compound III;
Wherein, hydrogen reducing described in step (1), refers under Lei Ni-Ni, ruthenium-carbon or Pd-C catalytic condition and carries out; The reduction of step (1) is carried out under C1-C4 alkanol exists, and preferably, in methyl alcohol or alcohol solvent, carries out;
Described in step (2), acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.;
The described reaction of step (2) is to carry out under the condition of organic bases or mineral alkali existence, and here, described organic bases is selected from triethylamine, DIPEA or pyridine, is preferably triethylamine; Described mineral alkali is selected from alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate, is preferably sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, more preferably sodium carbonate, salt of wormwood or sodium bicarbonate;
Described in step (3), recrystallization carries out in C1-C4 alkanol solvent.Described recrystallization can carry out in a kind of C1-C4 alkanol solvent, also can in the mixed solvent of two or more C1-C4 alkanols, carry out.Preferred described recrystallization carries out in methyl alcohol and/or ethanol, more preferably in methyl alcohol, carries out.
In a kind of particularly preferred embodiment, the invention provides the preparation method that a kind of Gastrodine key intermediate is compound III, formed by following steps:
(1), under hydrogen, Pd-C existence condition, Compound I is reduced in methanol solvate, obtain Compound I I;
(2), step (1) gained Compound I I and diacetyl oxide are carried out to acetylization reaction, obtain the crude product of compound III;
(3), by step (2) gained crude product, recrystallization in methanol solvate, obtains compound III sterling.
On the other hand, the invention provides the synthetic method of high purity Gastrodine, formed by the following step:
(1), by starting material compound I with hydrogen reducing, obtain Compound I I;
(2), Compound I I reacts with acetylation reagent, obtains compound III crude product;
(3), by step (2) gained compound III recrystallization, obtain the sterling of compound III;
(4), step (3) gained compound III is reacted in the C1-C4 of C1-C4 alkanol potassium or sodium alkanol system, obtain Gastrodine, preferably, at CH
3oNa/CH
3oH or C
2h
5oNa/CH
3cH
2in OH system, react.
Gastrodin Intermediate provided by the invention is the preparation method of compound III, and wherein, the reduction reaction of step (1), is to carry out under 40-50 DEG C of condition, and the reaction times is 4-8 hour.
Gastrodin Intermediate provided by the invention is the preparation method of compound III, and wherein, in step (2), the mol ratio that Compound I I and acetylation reagent feed intake is 1: 1.5～3, preferably, is 1: 1.6～2.5.
Gastrodin Intermediate provided by the invention is the preparation method of compound III, and wherein, described in step (2), the temperature of acetylization reaction is 85-100 DEG C, is preferably 90-100 DEG C.
Gastrodin Intermediate provided by the invention is the preparation method of compound III, and wherein, the time of acetylization reaction described in step (2) is 2-4h.
The synthetic method of Gastrodine provided by the invention, wherein, in step (4), the mol ratio that compound III and C1-C4 alkanol potassium or sodium feed intake is 1: 1.2-2.5, is preferably 1: 1.5-2.
The synthetic method of Gastrodine of the present invention, wherein, the described time of reacting in the C1-C4 of C1-C4 alkanol potassium or sodium alkanol system of step (4) is 3-5h, is preferably 4h; Reaction is carried out under reflux conditions being heated to.
Compared with prior art, Gastrodine key intermediate provided by the invention is the synthetic method of compound III and Gastrodine, its useful technique effect is embodied in: with hydrogen reducing Compound I, and the material bumping problem of having avoided document to cause with potassium borohydride reduction, and reduced production cost; In addition, the easy crystallization of compound III, purity are high, for obtaining the key operation of high purity Gastrodine, obtain Gastrodine by compound III deprotection, and without recrystallization again, products obtained therefrom purity is higher than standards of pharmacopoeia regulation, and Determination of Residual Organic Solvents is lower.Obtain compared with Gastrodine through the direct deprotection of Compound I I with literature method, Gastrodine preparation technology provided by the invention, products obtained therefrom content can reach more than 99.5%, and maximum single mixing is no more than 0.25%, total mixing is no more than 0.58%, and quality product is compared document has significance to promote; In addition, taking Compound I as starting raw material, this route yield can reach more than 90%.
Embodiment
Further describe the present invention by following concrete embodiment, but protection scope of the present invention is not limited by the following examples.
Proton nmr spectra instrument model used in an embodiment: Bruker Avance500 type NMR spectrometer with superconducting magnet.
HPLC adopts Agilent 1100.
The HPLC method for detecting purity of compound III in embodiment:
Liquid chromatography (LC) system adopts UV-detector, and detecting wavelength is 220nm and a stainless steel column that C18 fills, and flow velocity is 1.0ml/min, 30 DEG C of column temperatures.
The preparation of moving phase: phosphate buffered saline buffer (get SODIUM PHOSPHATE, MONOBASIC 1.56g, be dissolved in water and be diluted to 1000ml, mix rear with phosphoric acid tune pH to 4.0 ± 0.1)-acetonitrile (volume ratio is 50: 50) is moving phase, filters degassed for subsequent use.
The preparation of need testing solution: take trial-product 25mg, add 25ml chromatogram acetonitrile dissolve after as need testing solution.
Determination step: inject respectively blank solution, the need testing solution of equal-volume (20ul), record trial-product collection of illustrative plates, 40 minutes working times, deduction is blank, calculates the chromatographic purity of compound III by area normalization method.
Sample introduction sequence
| Sequentially | Solution | Pin number |
| 1 | Blank solution | 1 |
| 2 | Need testing solution | 1 |
Result judgement: chromatographic purity must not be less than 98.5%.
Fusing point test adopts capillary tube technique, and the melting range of described compound III is 121-125 DEG C.
4-formylphenyl-2,3,4,6-tetra--0-acetyl-β-D-glucopyranoside prepare reference: Zhou Jun, Yang Yanbin, Yang Chongren. the chemical research II of rhizoma Gastrodiae---Gastrodine and analogue thereof synthetic. chemical journal, 1980,32 (2): 162～166.
In following examples, unless stated otherwise, agents useful for same is all from being purchased.
In following examples, normal pressure refers to: 0.1MPa; Room temperature refers to: 25 DEG C.
Embodiment 1
(1) by 100g4-formylphenyl-2,3,4,6-tetra--0-acetyl-β-D-glucopyranoside, 600g methyl alcohol, 5g5% palladium carbon, at 45 DEG C, normal pressure passes into hydrogen, and insulation confined reaction is after 4 hours, filter, filtrate obtains Compound I I after 45-50 DEG C of concentrating under reduced pressure falls solvent.
(2) by product Compound I I, 200g aceticanhydride, 7g pyridine, be warmed up to 90-100 DEG C of reaction 3 hours, add 2000g purified water crystallization, filtration obtains obtaining the crude product of Gastrodin Intermediate compound III, then crude product is with obtaining Gastrodin Intermediate compound III after 120g95% ethyl alcohol recrystallization, 106.2g, yield 97.5%, it is 99.92% that HPLC detects purity.Through analyses such as fusing point detection, nucleus magnetic resonance, structure is consistent with target compound.
Fusing point is 123.3～124.1 DEG C;
1HNMR(500MHz，CDCl
3)δ7.28(d，J=7.0Hz，2H)，7.00(d，J=6.5Hz，2H)，5.31-5.27(m，1H)，5.20(t，J=9.5Hz，1H)，5.11(d，J=8.0Hz，1H)，5.08(s，2H)，4.27(dd，J=12.5Hz，3.3Hz，1H)，4.19(dd，J=12.0Hz，2.0Hz，1H)，3.89-3.84(m，1H)，2.08(s，3H)，2.06(s，3H)，2.05(s，3H)，2.04(s，6H)。
(3) compound III (100g, 0.186mol) after recrystallization is dissolved in the methyl alcohol that 350ml is dry, adds 20g sodium methylate, back flow reaction 4 hours, add acetic acid and adjust pH to neutral, filter, filtrate is concentrated, obtain Gastrodine 52.8g, yield 96%, fusing point: 153.5-154.5 DEG C, specific optical rotation :-68 °～-70 °, content 99.92% (content assaying method is shown in embodiment 4)
1hNMR (500MHz, CDCl
3) δ 7.20 (d, J=8.4Hz, 2H), 7.0 (d, J=8.4Hz, 2H), 4.82 (d, J=6.8Hz, 1H), 4.62 (s, 2H), 3.75 (t, J=6.8Hz, 1H), 3.70 (dd, J=6.8Hz, 1H), 3.36 (d, J=4.8Hz, 2H), 3.30 (t, 2H).
Embodiment 2
(1) by 100g4-formylphenyl-2,3,4,6-tetra--0-acetyl-β-D-glucopyranoside, 600g methyl alcohol, 12g Raney's nickel (the general Chemical Co., Ltd. in Dalian), at 40-50 DEG C, normal pressure passes into hydrogen, insulation confined reaction, after 8 hours, filters, and filtrate obtains Compound I I after 45-50 DEG C of concentrating under reduced pressure falls solvent.
(2) by compound 2,200g aceticanhydride, 9g triethylamine, be warmed up to 90-100 DEG C of reaction 3 hours, add 2000g purified water crystallization, filtration obtains obtaining the crude product of Gastrodin Intermediate compound III, then crude product obtains Gastrodin Intermediate compound III, 105.1g, yield 95.9% with after 120g95% ethyl alcohol recrystallization, it is 99.72% that HPLC detects purity, and fusing point is 122.9～123.7 DEG C.
(3) by the compound III (100g after recrystallization, 0.186mol) be dissolved in the ethanol that 350ml is dry, add 16g sodium ethylate, back flow reaction 4 hours, adding acetic acid adjusts pH to neutral, filter, filtrate is concentrated, obtains Gastrodine 52.6g, yield 95.8%, fusing point: 153.8-154.6 DEG C, specific optical rotation :-68～-70 °, content 99.98%.
Embodiment 3
(1) by 100g4-formylphenyl-2,3,4,6-tetra--0-acetyl-β-D-glucopyranoside, 800g ethanol, 5g5% ruthenium carbon (Pu Zhen bio tech ltd, Shanghai), at 40-50 DEG C, normal pressure passes into hydrogen, insulation confined reaction, after 4 hours, filters, and filtrate obtains Compound I I after 45-50 DEG C of concentrating under reduced pressure falls solvent.
(2) by Compound I I, 200g aceticanhydride, 7g pyridine, be warmed up to 90-100 DEG C of reaction 3 hours, add 2000g purified water crystallization, filtration obtains obtaining the crude product of Gastrodin Intermediate compound III, then crude product obtains Gastrodin Intermediate compound III, 105.0g, yield 95.7% with after 120g95% ethyl alcohol recrystallization, it is 99.68% that HPLC detects purity, and fusing point is 122.5～123.4 DEG C.
(3) by the compound III (100g after recrystallization, 0.186mol) be dissolved in the methyl alcohol that 350ml is dry, add 20g sodium methylate, back flow reaction 4 hours, adding acetic acid adjusts pH to neutral, filter, filtrate is concentrated, obtains Gastrodine 53g, yield 96.5%, fusing point: 153.5-154.6 DEG C, specific optical rotation :-68～-70 °, content 99.95%.
Embodiment 4 reference examples
The technical scheme being provided with patent application CN102516329A embodiment 1, prepares Gastrodine finished product, and lot number is 121001; Gastrodine prepared by the present embodiment 1-3, lot number is followed successively by 121002,121003,121004;
With reference to the Gastrodine national drug standards (WS1-XG-020-2001), with HPLC differential method, content, related substance to Gastrodine detect, and result is as shown in the table:
Know thus, gained Gastrodine finished product of the present invention is reaching pharmacopeia regulation aspect the content of content, related substance, and is far smaller than literature method (CN102516329A).
HPLC method detects gastrodin content condition and method in the present embodiment:
Chromatographic condition and system suitability octadecylsilane chemically bonded silica are weighting agent; Phosphoric acid solution-acetonitrile (97: 3) taking 0.05% is moving phase; Detection wavelength is 220nm; Number of theoretical plate calculates and should be not less than 3000 by Gastrodine peak.
Assay method is got this product 25mg, accurately weighed, put in 50ml measuring bottle, the phosphoric acid solution-acetonitrile (volume ratio is 97: 3) that adds moving phase 0.05% dissolves and is diluted to scale, shakes up, precision measures 5ml, put in 25ml measuring bottle, add moving phase and be diluted to scale, shake up, precision measures 20 μ l injection liquid chromatographies, records color atlas; Separately get Gastrodine reference substance (source: Chinese pharmaceutical biological product inspection institute) appropriate, be measured in the same method.Content by external standard method with Gastrodine and related substance in calculated by peak area trial-product.
Claims (9)
1. Gastrodine key intermediate is a preparation method for compound III, is made up of following steps:
(1), by starting material compound I with hydrogen reducing, obtain Compound I I;
(2), Compound I I reacts with acetylation reagent, obtains compound III crude product;
(3), by step (2) gained compound III crude product recrystallization, obtain the sterling of compound III.
2. preparation method as claimed in claim 1, wherein, hydrogen reducing described in step (1), refers under Raney's nickel, ruthenium-carbon or Pd-C catalytic condition and carries out; The reduction of step (1) is carried out under C1-C4 alkanol exists, and preferably, in methyl alcohol or alcohol solvent, carries out.
3. preparation method as claimed in claim 1, wherein, described in step (2), acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min..
4. preparation method as claimed in claim 1, wherein, reaction described in step (2) is to carry out under the condition of organic bases or mineral alkali existence, here, described organic bases is selected from triethylamine, DIPEA or pyridine, is preferably triethylamine; Described mineral alkali is selected from alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate, is preferably sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, more preferably sodium carbonate, salt of wormwood or sodium bicarbonate.
5. preparation method as claimed in claim 1, wherein, described in step (3), recrystallization carries out in C1-C4 alkanol solvent, and preferred described recrystallization carries out in methyl alcohol and/or ethanol, more preferably in methyl alcohol, carries out.
6. Gastrodine key intermediate is a preparation method for compound III, is made up of following steps:
(1), under hydrogen, Pd-C existence condition, Compound I is reduced in methanol solvate, obtain Compound I I;
(2), step (1) gained Compound I I and diacetyl oxide are carried out to acetylization reaction, obtain the crude product of compound III;
(3), by step (2) gained crude product, recrystallization in methanol solvate, obtains compound III sterling.
7. a synthetic method for high purity Gastrodine, is made up of the following step:
(1), by starting material compound I with hydrogen reducing, obtain Compound I I;
(2), Compound I I reacts with acetylation reagent, obtains compound III crude product;
(3), by step (2) gained compound III recrystallization, obtain the sterling of compound III;
(4), step (3) gained compound III is reacted in the C1-C4 of C1-C4 alkanol potassium or sodium alkanol system, obtain Gastrodine.
8. synthetic method as claimed in claim 7, wherein, hydrogen reducing described in step (1), refers under Lei Ni-Ni or Pd-C catalytic condition and carries out; The reduction of step (1) is carried out under C1-C4 alkanol exists, and preferably, in methyl alcohol or alcohol solvent, carries out;
Described in step (2), acetylation reagent is selected from diacetyl oxide or Acetyl Chloride 98Min.;
Reaction described in step (2) is to carry out under the condition of organic bases or mineral alkali existence, and here, described organic bases is selected from triethylamine, DIPEA or pyridine, is preferably triethylamine; Described mineral alkali is selected from alkali metal hydroxide, alkaline carbonate or alkali metal hydrocarbonate, is preferably sodium carbonate, salt of wormwood, sodium hydroxide, potassium hydroxide, sodium bicarbonate or saleratus, more preferably sodium carbonate, salt of wormwood or sodium bicarbonate;
Described in step (3), recrystallization carries out in C1-C4 alkanol solvent, and preferred described recrystallization carries out in methyl alcohol and/or ethanol, more preferably in methyl alcohol, carries out.
9. synthetic method as claimed in claim 7, wherein, the C1-C4 alkanol system of described C1-C4 alkanol potassium or sodium is CH
3oNa/CH
3oH system or C
2h
5oNa/CH
3cH
2oH system.
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| CN106905388A (en) * | 2017-02-16 | 2017-06-30 | 重庆西南制药二厂有限责任公司 | A kind of synthetic method of Gastrodin |
| CN111978361A (en) * | 2020-08-07 | 2020-11-24 | 天方药业有限公司 | Synthetic method of high-purity gastrodin |
| CN114478655A (en) * | 2022-01-04 | 2022-05-13 | 天方药业有限公司 | Preparation method of high-purity gastrodin hemihydrate |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106905388A (en) * | 2017-02-16 | 2017-06-30 | 重庆西南制药二厂有限责任公司 | A kind of synthetic method of Gastrodin |
| CN111978361A (en) * | 2020-08-07 | 2020-11-24 | 天方药业有限公司 | Synthetic method of high-purity gastrodin |
| CN114478655A (en) * | 2022-01-04 | 2022-05-13 | 天方药业有限公司 | Preparation method of high-purity gastrodin hemihydrate |
| CN114478655B (en) * | 2022-01-04 | 2023-12-26 | 天方药业有限公司 | Preparation method of high-purity gastrodin hemihydrate |
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