CN102875499B - The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof - Google Patents

The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof Download PDF

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CN102875499B
CN102875499B CN201110193550.6A CN201110193550A CN102875499B CN 102875499 B CN102875499 B CN 102875499B CN 201110193550 A CN201110193550 A CN 201110193550A CN 102875499 B CN102875499 B CN 102875499B
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trimethylene oxide
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aminomethyl
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CN102875499A (en
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甘伟
彭宣嘉
蔡亚仙
董径超
吴颢
马汝建
陈曙辉
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Wuxi Apptec Tianjin Co Ltd
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Abstract

The invention discloses the preparation method of a kind of 3-aminomethyl trimethylene oxide and oxalate and its acetate.Mainly solve the problem that should not amplify that existing preparation method exists, the present invention for starting raw material with compound 3-oxetanone, in the basic conditions, reacts with Nitromethane 99Min. and obtain 3-(Nitromethylene under the effect of methane sulfonyl chloride) trimethylene oxide.Afterwards under the effect of palladium hydroxide carbon and hydrogen, reduction obtains 3-aminomethyl trimethylene oxide, then with oxalic acid or acetic acid salify.Total recovery is 51%.

Description

The preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof
Technical field
The present invention relates to the preparation method of 3-aminomethyl trimethylene oxide and organic acid salt thereof, particularly the preparation method of 3-aminomethyl trimethylene oxide and oxalate/acetate thereof.
Background technology
Oxygen heterocycle butane occupies an important position in chemical synthetic drug with the structures and characteristics of its uniqueness, is also often found in natural product.Oxetane compound contains the strong Sauerstoffatom of electronegativity, makes it have larger polarity, is conducive to the lipotropy reducing drug molecule.The annular rigid structure that oxetane compound has makes it have enough volumes and occupies cavity.Its stable chemical property makes the metabolic stability of the drug molecule containing this structure greatly improve in addition.As or replace change (the Angew. Chem. Int. Ed. that similar pharmacophore unit (as gem-dimethyl and carbonyl functional group) can cause the character such as the pKa of medicine, water-soluble, fat-soluble, metabolic stability; 2006; 45,7736 – 7739; J. Med.Chem. 2010,53,3227-3246), form the molecule with special space configuration or conformation, thus the space structure of different biomacromolecule in organism can be mated, produce different physiologically actives or effectiveness.3-aminomethyl trimethylene oxide is the one in oxygen heterocycle butane, except containing except trimethylene oxide structure in its structure, also has an amino methyl, this makes it easily via acid amide condensation, the reaction of the classics such as reduction amination is incorporated in substrate molecule, solves the problem that butylene oxide ring structure is not easily directly synthesized.
Report the example that a gem-dimethyl is replaced by trimethylene oxide in document (J. Med.Chem. 2010,53,3227-3246), by table 1 data, we can be clearly seen that compound 2compare compound 1solubleness improve more than 20 times, the clearance rate in the liver of the mankind and mouse also reduces greatly, and pKa value is also corresponding simultaneously diminishes.
Table 1: compound 1 and 2 Data Comparison
Compound logD(logP) Solubleness Hepatic clearance (mankind/mouse) pKa
1 Undetermined 4 >1000/860 9.4
2 3.3（4.0） 91 42/380 8.0
Biological organic the report with pharmaceutical chemistry bulletin (Bioorganic & Medicinal Chemistry Letters, 2006,5968 – 5972) of document is pointed out, by compound 3substituting group on amide nitrogen changes into containing 3-aminomethyl oxetane derivative skeleton by ethyl, the compound obtained 4the inhibit activities of the target spot glycine transporter 1 that treatment mental disorder is correlated with is improve more than 7 times.
Patent WO2007125405 reports the amino condensed ring compounds of 2-of a series of replacement to the restraining effect of c-Jun N terminal kinase (JNK), is the medicine of the potential diabetes of a class and obesity.The compound that the butylene oxide ring wherein reported replaces 5inhibition concentration K i170 nM can be reached.
Patent WO2007002481 reports the drug molecule containing 3-aminomethyl trimethylene oxide skeleton 6to the acute HIV (human immunodeficiency virus) infection of suppression, there is activity, and there is no cytotoxicity.
Patent WO2010103279 reports the supression result of a series of 3-aminomethyl oxetane derivative to leukotrienes (Leukotriene C4 synthase, LTC4S).Such compounds exhibit goes out good activity, be expected to be applied to the relative disease that class is breathed in treatment, as LTRA, sugar, (cortical hormone, antihistaminic etc. and the relative disease for the treatment of inflammation class, as rheumatism, syndromes fash, NSAID (non-steroidal anti-inflammatory drug) etc.Wherein active best compound 7to the half-inhibition concentration IC of LTC4s 50=50 nM.
Orexin (Orexin) has multiple dysfunction of nervous regulation, not only can affect body feeding behavior, also participates in the adjustment of sleep-wake cycle, metabolism of blood glucose, pain perception, cardiovascular and autonomic adjustment etc.Patent US2009312314 reports the antagonistic of a series of potential Orexin acceptor, the compound of wherein butylene oxide ring replacement 10to inhibit activities Kb=26.3 nM of Orexin acceptor OX2R.
Described in upper, this segment continues to be applied more and more widely in recent years, as patent WO2010138589, WO2010065865, WO2005092881, WO2008138889, WO2010137351, WO2009067613, WO2010017401 etc. once used this fragment, and obtained good biological activity.
Be below disclosed with the closely-related synthetic method of the technology of the present invention in document.
Document Angew. Chem. Int. Ed., 2006,45,7736 report 3-(Nitromethylene) preparation of trimethylene oxide, see formula 1, this route is with compound 3-oxetanone 1for starting raw material, under the effect of the triethylamine of catalytic amount, obtain 3-(Nitromethane 99Min. with Nitromethane 99Min. (also as reaction solvent, greatly excessive) room temperature reaction) oxa-ring fourth-3-alcohol 2.Then compound 2in dichloromethane solvent, be cooled to-78 oc, adds the triethylamine of 4.4 equivalents and the methane sulfonyl chloride of 3 equivalents, finally obtains final product 3-(Nitromethylene with the yield of 81%) trimethylene oxide 3.It is 2.6 mmoles that the report raw material of this route feeds intake, and post-reaction treatment directly pours reaction solution in silicagel column purifying, and thus this process is not suitable for the amplification of reaction, has suitable limitation.
formula 1
。
Summary of the invention
The object of the invention is the preparation method being to provide a kind of 3-aminomethyl trimethylene oxide oxalate and acetate thereof.Mainly solve the problem that should not amplify that existing preparation method exists, the present invention uses the method for catalytic hydrogen reduction to obtain 3-aminomethyl trimethylene oxide to the reduction of one step, and attempts having synthesized its oxalate and acetate.
Technical scheme is: a kind of preparation method of 3-aminomethyl trimethylene oxide, comprises the following steps: with compound 3-oxetanone 1for starting raw material, under the basic cpd effect of catalytic amount, under room temperature (20-30 degree Celsius), be obtained by reacting 3-(Nitromethane 99Min. with Nitromethane 99Min.) oxa-ring fourth-3-alcohol 2.Then compound 2react with acylating reagent, dehydration immediately obtains 3-(Nitromethylene) trimethylene oxide 3.Compound 3under metal catalyst catalysis, hydrogen reducing obtains 3-aminomethyl trimethylene oxide 4; 3-aminomethyl trimethylene oxide oxalate can be obtained further with oxalic acid or acetic acid reaction 5with 3-aminomethyl trimethylene oxide acetate 6.Principal reaction formula is as follows:
Wherein the first step reaction is under the existence of basic cpd, and react in organic solvent, basic cpd used is the one in triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide or sodium acetate, is wherein preferably triethylamine.Solvent used is one or more in Nitromethane 99Min., methylene dichloride or tetrahydrofuran (THF), is wherein preferably Nitromethane 99Min..Reaction times used is 4 ~ 24 hours, is preferred with 10 hours.
Second step reaction, in the organic solvent of-78 DEG C, under the existence of basic cpd, is reacted with acylating reagent.Basic cpd used is the one in triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium acetate, salt of wormwood or sodium bicarbonate, is wherein preferably triethylamine.Acylating reagent used is the one in methane sulfonyl chloride, diacetyl oxide, trifluoromethanesulfanhydride anhydride or thionyl chloride, and wherein methane sulfonyl chloride is preferred reagent.Organic solvent used is one or more in methylene dichloride, acetic acid, ethanol, toluene, acetonitrile or tetrahydrofuran (THF), and wherein methylene dichloride is preferred solvent.Reaction times used is 4 ~ 20 hours, is preferred with 20 hours.
Three-step reaction is under the effect of metal catalyst, in organic solvent, obtains 3-aminomethyl trimethylene oxide with hydrogen reducing.Metal catalyst is palladium hydroxide carbon (mass percent 10%), palladium carbon (percent mass 10%), the one in Raney's nickel, with palladium hydroxide carbon (mass percent 10%) for optimum condition.Organic solvent used is the one in alcohols or esters solvent, take methyl alcohol as optimum condition.Hydrogen pressure is 1 ~ 6 normal atmosphere, with 4 normal atmosphere for optimum condition.Temperature of reaction is 20 ~ 50 DEG C, preferably 20 ~ 45 DEG C, is most preferably condition with 45 DEG C.Reaction times is 24 ~ 75 hours, preferably 24 ~ 50 hours, within 24 hours, to be most preferably condition.The 3-aminomethyl trimethylene oxide obtained after reaction is the sour salify with certain organic or inorganic again, and acid used is the one in oxalic acid, acetic acid, tosic acid, haloid acid, sulfuric acid, citric acid, tartrate or oxysuccinic acid, is preferred with oxalic acid or acetic acid.
Beneficial effect of the present invention: the feature of the present invention's and case of thermal instability low according to 3-aminomethyl trimethylene oxide boiling point, reaches the object of purification, for subsequent reactions provides reliable purity basis by the method for itself and oxalic acid or acetic acid salify.Existing document (Angew. Chem. Int. Ed., 2006, 45, 7736) 3-(Nitromethylene is reported) synthetic method of trimethylene oxide, through simultaneous test, we find, along with the increase (10 grams of starting raw material 3-oxetanones) of the scale of feeding intake, in this step reaction using methane sulfonyl chloride dehydration, the temperature of reaction is very large on yield impact, contrast discovery by experiment, using the methane sulfonyl chloride of dchloromethane and passing through slowly dropping makes in whole process warm lower than-70 DEG C in reaction, bibliographical information is different from after dripping, we adopt clear-cutting forestland to arrive ambient temperature overnight reaction, make final yield more than 60% by extending the reaction times.Although what require emphasis be a bit this compound is solid, its fusing point is lower, volatile, is easy to be taken away by vacuum in the solution.Then the synthesis of 3-aminomethyl trimethylene oxide falls nitro and double bond by a step catalytic hydrogen reduction.In the metal catalyst used, palladium hydroxide is optimal selection, uses during palladium carbon and only obtains final product in room temperature and 1 atmospheric hydrogen atmosphere, and heating or the reaction of increase hydrogen pressure all can become assorted.Raney's nickel is used not obtain pure product.Solvent is good with methyl alcohol, uses etoh solvent to react in a heated condition and becomes assorted.Consider that product boiling point is lower, for ease of the aftertreatment of reaction with the lower methyl alcohol of boiling point for optimum condition.Attempt using Lithium Aluminium Hydride and sodium borohydride to reduce 3-(Nitromethylene as reductive agent in addition) trimethylene oxide all do not have successfully.
The purity of hydro-reduction after product is from nuclear-magnetism more than 85%, and considering and improve the method not success that purity uses underpressure distillation further, may be that product heat is decomposed.By carrying out purified product with the method for organic acid or inorganic acids, be preferred by screening with oxalic acid and acetic acid.Free product and oxalic acid salify can obtain solid, but because the degree of every secondary response and aftertreatment may differences to some extent, and the amount adding oxalic acid is according to 3-(Nitromethylene) amount of trimethylene oxide feeds intake, therefore the amount of oxalic acid may have excessive, under this salt-forming condition, free oxalic acid also can be separated out, and is therefore difficult in product avoid free oxalic acid.
Product and acetic acid also can good salifies, and acetate can identify the content of its excessive free acetic acid according to the ratio at the methyl peak of acetic acid in nuclear magnetic spectrum and Product characteristics peak, solve the problem determining product actual content, for follow-up reaction and application are provided convenience.
Embodiment
Enumerate embodiment to be described in detail the present invention, but the present invention is not limited to these embodiments.
embodiment 1: 3-(Nitromethane 99Min.) preparation of oxa-ring fourth-3-alcohol
Operation steps: in the single port bottle of 250 milliliters, adds Nitromethane 99Min. (36 milliliters) and 3-oxetanone 1(3.7 grams, 51.3 mmoles), add triethylamine (70 milligrams), room temperature reaction 10 hours under stirring.Reaction solution vacuum is revolved and steams the excessive Nitromethane 99Min. of removing, obtain 6.8 grams of weak yellow liquid 3-(Nitromethane 99Min.s) oxa-ring fourth-3-alcohol 2, yield 100%.
HNMR (CDCl 3) δ4.83 (s, 2H), 4.72 (d, J = 8.0 Hz, 2H), 4.60 (d, J = 8.0 Hz, 2H)。
embodiment 2: 3-(Nitromethylene) preparation of trimethylene oxide
In the there-necked flask of 1 liter, add methylene dichloride (300 milliliters) and 3-(Nitromethane 99Min.) oxa-ring fourth-3-alcohol (6.8 grams, 51.3 mmoles), with dry ice acetone bath Leng Que Dao – 78 DEG C.Then be added dropwise to triethylamine (15.6 grams, 154 mmoles), be slowly added dropwise to methylene dichloride (80 milliliters) solution of methane sulfonyl chloride (11.8 grams, 104 mmoles) afterwards, dropwise in 3 hours.Continue stirring reaction at adding Hou – 78 DEG C 2 hours, clear-cutting forestland was to stirring at room temperature 12 hours.Reaction solution is poured into cancellation in frozen water, add methylene chloride extraction.Organic phase uses saturated common salt water washing, filters after anhydrous sodium sulfate drying.After filtrate decompression is steamed and desolventized, through purification by column chromatography.Eluent is sherwood oil: ethyl acetate=15:1.Finally obtain 3.8 grams of white solid product, yield 64%.
HNMR (CDCl 3) δ 6.92 (m, 1H), 5.66 (m, 2H), 5.38 (m, 2H)。
embodiment 3: the preparation (palladium hydroxide carbon and methyl alcohol, room temperature, hydrogen 1 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation steps: 3-(Nitromethylene) trimethylene oxide 3the palladium hydroxide carbon (mass percent 10%) of (0.88 gram, 7.7 mmoles) and 0.3 gram adds in reaction flask, adds the methyl alcohol of 20 milliliters, filters after 1 atmospheric hydrogen at room temperature stirs 48 hours.Filter cake methyl alcohol thoroughly washs, and the filtrate decompression of gained obtains colourless liquid 1.2 grams (remaining solvent methanol) after steaming and desolventizing.
HNMR (MeOD) δ4.80 (t, J= 6.4 Hz, 2H), 4.40 (t, J= 6 Hz, 2H), 3.05 (m, 1H), 2.97 (t, J= 7.2 Hz, 2H)。
Aforesaid liquid is dissolved in 10 milliliters of t-butyl methyl ether, then the anhydrous oxalic acid (0.34 gram will be dissolved in about 2 milliliters ethanol, 3.8 mmoles) solution adds in above-mentioned solution, adularescent solid is separated out at once, filter, obtain 0.7 gram of white solid after filtration cakes torrefaction, be 3-aminomethyl trimethylene oxide oxalate (may part oxalic acid be contained), yield 73 %.
HNMR (D 2O) δ4.90 (m, 2 H), 4.52 (m, 2H), 3.38 (m, 3H)。
embodiment 4: the preparation (palladium hydroxide carbon and methyl alcohol, room temperature, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation steps: operate same embodiment 3, hydrogen pressure is increased to 4 normal atmosphere, 3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium hydroxide carbon (mass percent 10%) is 0.1 gram, room temperature reaction 40 hours, yield 55%.
embodiment 5: the preparation (palladium hydroxide carbon and ethanol, room temperature, hydrogen 1 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium hydroxide carbon (mass percent 10%) is 0.1 gram, and etoh solvent is 10 milliliters, room temperature reaction 45 hours, yield 75%.
embodiment 6: the preparation (palladium hydroxide carbon and methyl alcohol, 45 DEG C, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium hydroxide carbon (mass percent 10%) is 0.1 gram, and solvent methanol is 10 milliliters, reacts 24 hours, yield 80% under 45 ° of C and 4 atmospheric hydrogen atmosphere.
embodiment 7: the preparation (palladium hydroxide carbon and ethyl acetate, 45 ° of C, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium hydroxide carbon (mass percent 10%) is 0.1 gram, and solvent ethyl acetate is 10 milliliters, react 24 hours under 45 ° of C and 4 atmospheric hydrogen atmosphere, yield 65%.
embodiment 8: the preparation (palladium carbon and methyl alcohol, room temperature, hydrogen 1 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium carbon (mass percent 10%) is 0.1 gram, and solvent methanol is 10 milliliters, reaction 50 hours under room temperature and 1 atmospheric hydrogen atmosphere, yield 45%.
embodiment 9: the preparation (palladium carbon and methyl alcohol, room temperature, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium carbon (mass percent 10%) is 0.1 gram, and solvent methanol is 10 milliliters, and reaction 50 hours under room temperature and 4 atmospheric hydrogen atmosphere, yield is less than 30%.
embodiment 10: the preparation (palladium carbon and methyl alcohol, 45 ° of C, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium carbon mass percent 10%) be 0.1 gram, solvent methanol is 10 milliliters, react 50 hours under room temperature and 4 atmospheric hydrogen atmosphere, nuclear-magnetism display 3-aminomethyl trimethylene oxide content is less than 10%, non-salify.
embodiment 11: the preparation (Raney's nickel and methyl alcohol, room temperature, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, Raney's nickel is 0.1 gram, and solvent methanol is 10 milliliters, and reaction 5 hours under room temperature and 4 atmospheric hydrogen atmosphere, nuclear-magnetism display reaction is very assorted, does not have obvious product.
embodiment 12: the preparation (Raney's nickel and methyl alcohol, 45 ° of C, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide oxalate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, Raney's nickel is 0.1 gram, and solvent methanol is 10 milliliters, reacts 5 hours under 45 ° of C and 4 atmospheric hydrogen atmosphere, and nuclear-magnetism display reaction is very assorted, does not have obvious product.
embodiment 13: the preparation (palladium hydroxide and methyl alcohol, 45 ° of C, hydrogen 4 normal atmosphere) of 3-aminomethyl trimethylene oxide acetate
Operation is with embodiment 3,3-(Nitromethylene) trimethylene oxide charging capacity is 0.3 gram, palladium hydroxide (mass percent 10%) is 0.1 gram, solvent methanol is 10 milliliters, react 24 hours under 45 ° of C and 4 atmospheric hydrogen atmosphere, Glacial acetic acid (0.2 gram), yield 80%(has residual free acetic acid).
HNMR (MeOD) δ4.62 (m, 2 H), 4.26 (m, 2H), 3.09~3.13(m, 3H), 1.75 (s, 4H)。

Claims (10)

  1. The preparation method of 1.3-aminomethyl trimethylene oxide, is characterized in that, comprise the following steps:
    The first step: with compound 3-oxetanone for starting raw material, under basic cpd condition, be obtained by reacting 3-(nitromethyla with Nitromethane 99Min. in a solvent) oxa-ring fourth-3-alcohol;
    Second step: 3-(nitromethyla) oxa-ring fourth-3-alcohol under basic cpd condition, be obtained by reacting 3-(Nitromethylene with acylating reagent in a solvent) trimethylene oxide;
    3rd step: 3-(Nitromethylene) trimethylene oxide under metal catalyst catalysis, obtain 3-aminomethyl trimethylene oxide with hydrogen reducing in organic solvent; Described metal catalyst is palladium hydroxide carbon or palladium carbon.
  2. The preparation method of 2.3-aminomethyl trimethylene oxide oxalate and acetate thereof, is characterized in that, comprise the following steps:
    The first step: with compound 3-oxetanone for starting raw material, under basic cpd condition, be obtained by reacting 3-(nitromethyla with Nitromethane 99Min. in a solvent) oxa-ring fourth-3-alcohol;
    Second step: 3-(nitromethyla) oxa-ring fourth-3-alcohol under basic cpd condition, be obtained by reacting 3-(Nitromethylene with acylating reagent in a solvent) trimethylene oxide;
    3rd step: 3-(Nitromethylene) trimethylene oxide is under metal catalyst catalysis, and obtain 3-aminomethyl trimethylene oxide with hydrogen reducing in organic solvent, described metal catalyst is palladium hydroxide carbon or palladium carbon;
    4th step: 3-aminomethyl trimethylene oxide and oxalic acid or acetic acid reaction obtain 3-aminomethyl trimethylene oxide oxalate or 3-aminomethyl trimethylene oxide acetate .
  3. 3. preparation method according to claim 1 and 2, it is characterized in that, the first step basic cpd used is the one in triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide or sodium acetate, solvent used is one or more in Nitromethane 99Min., methylene dichloride or tetrahydrofuran (THF), and the reaction times used is 4 ~ 20 hours.
  4. 4. preparation method according to claim 3, is characterized in that, the first step basic cpd used is triethylamine, and solvent used is Nitromethane 99Min., and the reaction times used is 10 hours.
  5. 5. preparation method according to claim 1 and 2; it is characterized in that; second step basic cpd used is the one in triethylamine, diisopropylethylamine, pyridine, sodium hydroxide, potassium hydroxide, sodium acetate, salt of wormwood or sodium bicarbonate; acylating reagent used is the one in methane sulfonyl chloride, diacetyl oxide, trifluoromethanesulfanhydride anhydride or thionyl chloride; solvent used is one or more in methylene dichloride, acetic acid, ethanol, toluene, acetonitrile or tetrahydrofuran (THF), and the reaction times used is 4 ~ 20 hours.
  6. 6. preparation method according to claim 5, is characterized in that, second step basic cpd used is triethylamine, and acylating reagent used is methane sulfonyl chloride, and solvent used is methylene dichloride, and the reaction times used is 20 hours.
  7. 7. preparation method according to claim 1 and 2, is characterized in that, described three-step reaction organic solvent used is alcohols or esters solvent, and temperature of reaction used is 20 ~ 50 DEG C, and the reaction times used is 24 ~ 75 hours.
  8. 8. preparation method according to claim 1 and 2, is characterized in that, metal catalyst used is the palladium hydroxide carbon of mass percent 10%.
  9. 9. preparation method according to claim 7, is characterized in that, described three-step reaction organic solvent used is methyl alcohol, and temperature of reaction is 20 ~ 45 DEG C, and the reaction times used is 24 ~ 50 hours.
  10. 10. preparation method according to claim 9, is characterized in that, described three-step reaction temperature is 45 DEG C, and the reaction times used is 24 hours.
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