CN1422847A - Epiphysin synthesis method - Google Patents
Epiphysin synthesis method Download PDFInfo
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- CN1422847A CN1422847A CN 01140243 CN01140243A CN1422847A CN 1422847 A CN1422847 A CN 1422847A CN 01140243 CN01140243 CN 01140243 CN 01140243 A CN01140243 A CN 01140243A CN 1422847 A CN1422847 A CN 1422847A
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- CN
- China
- Prior art keywords
- methoxytryptamine
- epiphysin
- chloropropyl
- diethyl malonate
- solution
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- Pending
Links
- 238000001308 synthesis method Methods 0.000 title 1
- -1 2-ethyl Chemical group 0.000 claims abstract description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 8
- 230000008569 process Effects 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000020477 pH reduction Effects 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- JTEJPPKMYBDEMY-UHFFFAOYSA-N 5-methoxytryptamine Chemical compound COC1=CC=C2NC=C(CCN)C2=C1 JTEJPPKMYBDEMY-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 10
- 229940097276 5-methoxytryptamine Drugs 0.000 claims description 9
- 238000010189 synthetic method Methods 0.000 claims description 9
- KTMYIILZMFFVEX-UHFFFAOYSA-N 2-(2-ethoxycarbonyl-5-methoxy-1h-indol-3-yl)ethylazanium;chloride Chemical compound [Cl-].C1=C(OC)C=C2C(CC[NH3+])=C(C(=O)OCC)NC2=C1 KTMYIILZMFFVEX-UHFFFAOYSA-N 0.000 claims description 8
- 230000015572 biosynthetic process Effects 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000011259 mixed solution Substances 0.000 claims description 7
- 238000010992 reflux Methods 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 238000006555 catalytic reaction Methods 0.000 claims description 6
- 238000005660 chlorination reaction Methods 0.000 claims description 6
- MFESCIUQSIBMSM-UHFFFAOYSA-N I-BCP Chemical compound ClCCCBr MFESCIUQSIBMSM-UHFFFAOYSA-N 0.000 claims description 5
- AGBWAVXRUQFCEX-UHFFFAOYSA-N NN.C1(=CC=CC=C1)OC Chemical compound NN.C1(=CC=CC=C1)OC AGBWAVXRUQFCEX-UHFFFAOYSA-N 0.000 claims description 5
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 5
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229960004756 ethanol Drugs 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 238000013019 agitation Methods 0.000 claims description 3
- 239000003637 basic solution Substances 0.000 claims description 3
- 238000006193 diazotization reaction Methods 0.000 claims description 3
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 claims description 3
- 229940067157 phenylhydrazine Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 102000004190 Enzymes Human genes 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 238000010719 annulation reaction Methods 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
- 235000011149 sulphuric acid Nutrition 0.000 claims description 2
- APJYDQYYACXCRM-UHFFFAOYSA-N tryptamine Chemical compound C1=CC=C2C(CCN)=CNC2=C1 APJYDQYYACXCRM-UHFFFAOYSA-N 0.000 abstract 4
- 239000000460 chlorine Substances 0.000 abstract 3
- 229910052801 chlorine Inorganic materials 0.000 abstract 3
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 abstract 2
- 150000002148 esters Chemical class 0.000 abstract 2
- PVRSIFAEUCUJPK-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine Chemical compound COC1=CC=C(NN)C=C1 PVRSIFAEUCUJPK-UHFFFAOYSA-N 0.000 abstract 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract 1
- 239000001294 propane Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 7
- 229940088597 hormone Drugs 0.000 description 6
- 239000005556 hormone Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 5
- 210000004560 pineal gland Anatomy 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000003908 quality control method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229960003987 melatonin Drugs 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 230000036039 immunity Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000005172 vertebrate brain Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention refers to a synthesizing method of pineal element. The steps as follows: a. make diethyl malonate or acetylacetic ester react with 1-Br-3-chlorine propane to obtain 3-chlorine propy diethyl malonate or 3-chlorine propyl acetylacetic ester; b, making loop reaction on the resultant and p-methoxyl phenyl hydrazine in potassium hydroxide alcohol solution, then make the acidification process to obtain 2-ethyl oxyyl carboxyl-5-methoxyl tryptamine hydrogen-chloride; c. making further saponfiication and acidification process to obtain 5-methyoxyl tryptamine; d, make further acetylization to obtain conarium element.
Description
Technical field:
The present invention relates to a kind of synthetic method of epiphysin.
Background technology:
Epiphysin (melatonin) has another name called epiphysin or melatonin or Mei Tongning or Melatonin, is the synthetic and a kind of indoles hormone of excretory of pineal gland in the vertebrate brain, and chemical name is N-ethanoyl-5-methoxytryptamine.Both at home and abroad this hormone study was used in nearly 20 years and shown: epiphysin synthetic and secretion in animal body mainly is to be regulated by the diel rhythm that pineal gland and retina are experienced ambient light.The epiphysin that pineal gland is secreted is out commanded other hormone, makes other hormone keep normal concentration and circulation, and other hormone is then controlled the function of human body.Epiphysin is controlled the function of human body whole body indirectly by influencing other hormone, thereby becomes one of the highest dominant force of human body.Epiphysin is controlled immunity system and energy system simultaneously, and effect such as anti-nervous compressing grade is arranged again, and these systems and physiological function are by pineal gland usually " leader ", cooperatively interact, act in concert with each other, the coordination of keeping the bodily fuctions jointly reaches the purpose that the people is had good health and a long life with stable.Epiphysin participates in the multiple physiological activity of body, to keeping ortho and 24 hours biorhythms play keying action.After people in middle age, its secretory volume descends, then wait for the organ or tissue that epiphysin is supplied with, also and then aging and break down, thus many physiological function detuning phenomenas produced, such as somnopathy, energy and immunity degradation etc.External source feeds epiphysin can improve above-mentioned symptom.
The epiphysin route of administration is very extensive, and oral, subcutaneous injection, transdermal administration and intranasal administration all can.Its major function has: hypnosis, correction time difference sense of discomfort, delay senility, improve immunologic function, the control mankind and animal are stepped into the numerous disease that takes place old and feeble period, can be anticancer, control cholesterol, inhibition heart trouble are prevented and treated atherosclerosis, coronary heart disease, apoplexy, prevent and treat hypertension and improve sexual function.Epiphysin becomes one of focus of now human and 21st century concern because of its hypnosis that has and the anti-ageing important physiological action and almost having no side effect of waiting for a long time, and as a kind of health care medicine and the fashionable whole world of food.
It is that pineal gland from animal brain extracts that epiphysin begins, but the biological extraction source is limited, the cost height, yields poorly.The method mass production of present available chemosynthesis abroad mainly is to be that raw material synthesizes with 5-methoxyl group indoles, or with the serotonin back amidation preparation that methylates.These synthetic route repeatability are relatively poor, raw material sources difficulty and expensive, and method for preparing raw material is more loaded down with trivial details, and synthesis step is many, generally need 10 above reactions of step to finish, and reaction conditions is wayward.The domestic market supply is main by import.Therefore, seek an economical and practical synthesis route and become the important topic that people pay close attention to.
Summary of the invention:
The objective of the invention is to overcome the above-mentioned shortcoming of prior art, the synthetic method of a kind of economy, easy epiphysin is provided.
For achieving the above object, the synthetic method of epiphysin of the present invention comprises following synthesis step successively:
A, diethyl malonate or methyl aceto acetate obtain 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate with the reaction of 1-bromo-3-chloropropane;
B, 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate with the methoxyl group phenylhydrazine is carried out annulation in the ethanolic soln of potassium hydroxide, and through acidification, thereby make 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride;
C, 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride makes the 5-methoxytryptamine through saponification and acidification;
D, 5-methoxytryptamine make epiphysin through acetylize again.
As optimization, described synthesis step:
A is: slowly add sodium ethylate under stirring in the mixed solution of diethyl malonate or methyl aceto acetate and 1-bromo-3-chloropropane, after the stirring and refluxing reaction, steam ethanol, again through refining 3-chloropropyl diethyl malonate or the 3-chloropropyl methyl aceto acetate of obtaining;
B comprises step by step following:
(1) 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate solution are removed moisture in dehydrated alcohol, add KOH again and are made into basic solution;
(2) P-nethoxyaniline is dissolved in water and the concentrated hydrochloric acid, at low temperatures with NaNO
2The aqueous solution slowly be added drop-wise in the mixed solution of above-mentioned P-nethoxyaniline, low temperature is finished diazotization, uses Na again
2CO
3Regulate pH value to 6, temperature is lower than 0 ℃, gets chlorination to the anisole hydrazine solution;
(3) (1) step product is cooled to-5 ℃, under agitation drips chlorination, regulate the pH value, leave standstill, again the pH value is adjusted to 6 to 7.4-7.5 to the anisole hydrazine solution, after room temperature leaves standstill again through separation purify 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride;
C is: 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride is dissolved in the NaOH solution, the reflux postcooling, again with re-refine behind the acidifying with acetic acid product; Aforementioned product is added back flow reaction in the dilute sulphuric acid, be basified to pH value to 9 with NaOH again, after purifying, get the 5-methoxytryptamine;
D is: the 5-methoxytryptamine is dissolved in the mixed solution of benzene and pyridine, drips acetic acid in ice bath, remove behind the ice bath again through stirring reaction, after refining epiphysin.
As optimization, described synthesis step uses ultrasonic wave or microwave or infrared or physical means such as ultraviolet or laser, or adopt biocatalysis such as enzyme or microorganism or adopt new chemical catalysis, or both or many persons' of physics, chemistry and biological three major types catalysis process reasonable combination is used the process that adds fast response.
With the synthetic epiphysin of this processing method, mild condition and raw material are easy to get, and have shortened reactions steps, have reduced the production cost of unit product, have improved productivity.The reaction ultrasonic wave catalysis of first to five step, third and fourth and the reaction of five steps can be shortened the reaction times so greatly with microwave or infrared catalysis, improve reaction yield.
Therefore, the synthetic method of epiphysin of the present invention has mild condition, and raw material is easy to get, and reactions steps is few, and is workable, and is economical simple and easy, and the productivity height can shorten reaction times and the advantage that improves yield greatly.
Embodiment:
The synthetic method of epiphysin of the present invention can be further specified with following examples;
With diethyl malonate and P-nethoxyaniline is starting raw material, synthesizes epiphysin (N-ethanoyl-5-methoxytryptamine) through five step reaction process.The synthetic route of design is as follows:
1,3-chloropropyl-diethyl malonate (II) is synthetic
The sodium Metal 99.5 of 138g (6.0mol) is cut into pieces, put in the 2.5L dehydrated alcohol, make fresh alcohol sodium solution. under agitation alcohol sodium solution slowly is added drop-wise in the mixed solution of 960g (6.0mol) diethyl malonate (I) and 944g (6.0mol) 1-bromo-3-chloropropane, stirring and refluxing 2h, steam and remove ethanol, be chilled to room temperature, add 1L cold water, separatory, water layer merges organic layer with 5L extracted with diethyl ether (3 times), uses anhydrous sodium sulfate drying, filter underpressure distillation.Productive rate is 60.2%, and b p.147-149
10 ℃, n
D 20.1.4429, IR (film, cm
-1) C=O:1738,1707.
1H NMR (CCl
4, δ ppm) and 4.15 (4H, q, COOCH
2CH
3), 3.54 (2H, t, Cl-CH
2), 1.30 (6H, t, COOCH
2CH
3).Industrial production quality control boiling point and refractive index.
2,2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride (III) is synthetic
2.37Kg (10mol) 3-chloropropyl diethyl malonate (II) is dissolved in the 7L dehydrated alcohol, removes moisture, drip 640gKOH and be dissolved in the solution that is made in the 7L dehydrated alcohol stirring to stop, continue to stir 2h.
By following process prepare chlorination to anisole hydrazine solution: 1.23kg (10mol) just the fresh P-nethoxyaniline crossed of purifying be dissolved in 10L water and the 2.7L concentrated hydrochloric acid; With 700g (11mol) NaNO
2The solution that is made into 1.5L water slowly is added drop-wise in the P-nethoxyaniline, and maintains the temperature at 0-3 ℃.Diazotization reaction finishes, and uses 10%NaCO
3Solution (about 7.7L) is regulated pH value to 6, and temperature is lower than 0 ℃.
The basic solution of Compound I I is cooled to-5 ℃, drips chlorination to the methoxyl group phenylhydrazine in whipping process, and the pH value of mixing solutions is with 10% NaCO
3(about 1.5L) transfers to 7.4-7.5, keeps system temperature to reach 1h for 0 ℃ filling under the nitrogen condition, is 6 with acidifying with acetic acid to pH value, moves on in the room temperature then and spends the night.Dilute with water, with the oily throw out of dichloromethane extraction reddish black, organic phase is washed with 2N NaOH, water (3 1L); MgSO
4Drying, the pressure reducing and steaming solvent; The reddish black residue heats in 16L ebullient propyl carbinol, fill nitrogen reaches 24h.Solution is cooled to 0 ℃, product I II crystallization; Concentrated mother liquor (volume reduces half) can obtain product I II again, and overall yield is 20.6%, mp.225 ℃ (using ethyl alcohol recrystallization).Ultimate analysis C
14H
19ClN
2O
3(M=298.8): calc.C56.40, H6.42, N9.40; FoundC56.20, H6.45, N9.52.IR (KBr, cm
-1) NH3450,3350,3200; C=C1695,1470; C-O1175.
1HNMR (DMSO-d
6, δ ppm) and-0.42 (1H, s, indole NH), 7.85-6.74 (3H, m, ArH), 4.26 (2H, q, COOCH
2CH
3), 3.50-2.70 (4H, m, CH
2CH
2), 3.73 (3H, s, OCH
3), 1.30 (6H, t, COOCH
2CH
3).Industrial production quality control fusing point.
3,5-methoxytryptamine (V) is synthetic
3.7mol compound III is dissolved in 4N NaOH (10L) solution, reflux 2h is chilled to 0 ° of C then, uses acidifying with acetic acid, obtains compound IV, mp.247-248 ℃.
The 4h 2.4mo compound IV refluxes in the sulfuric acid of 10L15% is 9 with the dense sodium hydroxide pH that alkalizes then; Isolate throw out, the extract evaporating solvent provides secondary product, adds up to yield 85%.Mp.120-121 ℃, IR (nujol.cm
-1) NH3310,3250,3080; C=C (phenyl ring) 1620,1585,1495; C-O:1240,1220; C-H (phenyl ring replacement) 860,850,813,793 (acidified mother liquor, recyclable compound IV).Industrial production quality control fusing point.
4, N-ethanoyl-5-methoxytryptamine (VI) is synthetic
5.2mol compound V is dissolved in 0.8L benzene and the 0.2L pyridine, drips 100mL acetic acid with ice-cooled back; Dropwise, remove ice bath, continue to stir 3h, volatile matter is removed in decompression, the residuum chloroform extraction, and use 5% NaHCO successively
3With saturated NaCl solution washing, after the dried over sodium sulfate, evaporating solvent, thick product benzene recrystallization, productive rate 99.1%, mp.116-118 ℃, ultimate analysis C
16H
16N
2O
2(M=232.28): calc.C67.20, H6.79, N11.89; Found C67.01, H6.78.N11.64.IR (KBr, cm
-1) NH3240, C=O1627 (primary amine); 1555 (secondary amines); C=C (phenyl ring) 1620,1587,1492; C-O:1217,1180; C-H (phenyl ring replacement): 828,810,800.
1H NMR[(CD
3)
2CO, δ ppm] 10.06 (1H, brs, phNH), 7.44 (1H, d, NH), 7.27 (1H, s, C
7H=), 7.12 (1H, s, C
4H=), 6.74 (1H, d, CH=, J=8.5Hz), 3.81 (3H, s, CH
3), 3.45 (2H, dd, CH
2, J=7Hz), 2.88 (2H, t, CH
2, J=7Hz), 1.89 (3H, s, CH
3).
1HNMR (CDCl
3, δ ppm) 8.10 (1H, s, NH), 7.28 (1H, s, H
2), 7.02 (1H, t, H
5), 6.59 (1H, d, H
4), 6.88 (1H, d, H
3), 5.82 (1H, s, NH), 3.86 (3H, s, OCH
3), 3.60 (2H, q, CH
2NH), 2.94 (2H, t, CH
2), 1.94 (3H, s, COCH
3). mass spectrum (M
+) (m/z): the 190.HPLC analysis condition: ODS post 15 0.5cm, moving phase is second eyeball-methanol-water (45: 40: 15), and column temperature 37+1 ℃, post is pressed 4000Psi, and solvent is a methyl alcohol, and the relative retention time of epiphysin is 1.085.Industrial production quality control fusing point is used high-pressure liquid chromatography in case of necessity.
Claims (3)
1, a kind of synthetic method of epiphysin is characterized in that comprising successively following synthesis step:
A, diethyl malonate or methyl aceto acetate obtain 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate with the reaction of 1-bromo-3-chloropropane;
B, 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate with the methoxyl group phenylhydrazine is carried out annulation in the ethanolic soln of potassium hydroxide, and through acidification, thereby make 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride;
C, 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride makes the 5-methoxytryptamine through saponification and acidification;
D, 5-methoxytryptamine make epiphysin through acetylize again.
2, the synthetic method of epiphysin according to claim 1 is characterized in that described synthesis step:
A is: slowly add sodium ethylate under stirring in the mixed solution of diethyl malonate or methyl aceto acetate and 1-bromo-3-chloropropane, after the stirring and refluxing reaction, steam ethanol, again through refining 3-chloropropyl diethyl malonate or the 3-chloropropyl methyl aceto acetate of obtaining;
B comprises step by step following:
(1) 3-chloropropyl diethyl malonate or 3-chloropropyl methyl aceto acetate solution are removed moisture in dehydrated alcohol, add KOH again and are made into basic solution;
(2) P-nethoxyaniline is dissolved in water and the concentrated hydrochloric acid, more at low temperatures with NaNO
2The aqueous solution slowly be added drop-wise in the mixed solution of above-mentioned P-nethoxyaniline, low temperature is finished diazotization, uses Na again
2CO
3Regulate pH value to 6, temperature is lower than 0 ℃, gets chlorination to the anisole hydrazine solution;
(3) (1) step product is cooled to-5 ℃, under agitation drips chlorination, regulate the pH value, leave standstill, again the pH value is adjusted to 6 to 7.4-7.5 to the anisole hydrazine solution, after room temperature leaves standstill again through separation purify 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride;
C is: 2-ethoxy carbonyl-5-methoxytryptamine hydrogenchloride is dissolved in the NaOH solution, the reflux postcooling, again with re-refine behind the acidifying with acetic acid product; Aforementioned product is added back flow reaction in the dilute sulphuric acid, be basified to pH value to 9 with NaOH again, after purifying, get the 5-methoxytryptamine;
D is: the 5-methoxytryptamine is dissolved in the mixed solution of benzene and pyridine, drips acetic acid in ice bath, remove behind the ice bath again through stirring reaction, after refining epiphysin.
3, the synthetic method of epiphysin according to claim 1 and 2, it is characterized in that described synthesis step uses ultrasonic wave or microwave or infrared or physical means such as ultraviolet or laser, or adopt biocatalysis such as enzyme or microorganism or adopt new chemical catalysis, or both or many persons' of physics, chemistry and biological three major types catalysis process reasonable combination is used the process that adds fast response.
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|---|---|---|---|
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 01140243 CN1422847A (en) | 2001-12-07 | 2001-12-07 | Epiphysin synthesis method |
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|---|---|
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ID=4675746
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN105708843A (en) * | 2016-04-07 | 2016-06-29 | 任永春 | Drug containing melatonin and phosphatidylserine |
| CN117049993A (en) * | 2023-10-11 | 2023-11-14 | 潍坊海通新材料科技有限公司 | Preparation method of melatonin |
-
2001
- 2001-12-07 CN CN 01140243 patent/CN1422847A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104496882A (en) * | 2014-11-29 | 2015-04-08 | 湖北金赛药业有限公司 | Synthesis method of melatonin |
| CN105708843A (en) * | 2016-04-07 | 2016-06-29 | 任永春 | Drug containing melatonin and phosphatidylserine |
| CN117049993A (en) * | 2023-10-11 | 2023-11-14 | 潍坊海通新材料科技有限公司 | Preparation method of melatonin |
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