CN1539823A - Method for preparing new demethyl conclaurine and medinal salt - Google Patents
Method for preparing new demethyl conclaurine and medinal salt Download PDFInfo
- Publication number
- CN1539823A CN1539823A CNA2003101016494A CN200310101649A CN1539823A CN 1539823 A CN1539823 A CN 1539823A CN A2003101016494 A CNA2003101016494 A CN A2003101016494A CN 200310101649 A CN200310101649 A CN 200310101649A CN 1539823 A CN1539823 A CN 1539823A
- Authority
- CN
- China
- Prior art keywords
- dimethoxy
- methoxyl group
- preparation
- benzyl
- demethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 title description 9
- 238000000034 method Methods 0.000 title description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-M 5,5-diethyl-4,6-dioxo-1h-pyrimidin-2-olate Chemical class CCC1(CC)C(=O)NC([O-])=NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-M 0.000 title 1
- WZRCQWQRFZITDX-UHFFFAOYSA-N (RS)-norcoclaurine Chemical compound C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 WZRCQWQRFZITDX-UHFFFAOYSA-N 0.000 claims abstract description 16
- WZRCQWQRFZITDX-AWEZNQCLSA-N Norcoclaurine Natural products C1=CC(O)=CC=C1C[C@H]1C2=CC(O)=C(O)C=C2CCN1 WZRCQWQRFZITDX-AWEZNQCLSA-N 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- 238000009833 condensation Methods 0.000 claims abstract description 6
- 230000005494 condensation Effects 0.000 claims abstract description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 8
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000017858 demethylation Effects 0.000 abstract 1
- 238000010520 demethylation reaction Methods 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000011084 recovery Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- -1 methoxyl groups Chemical group 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- VPKAHUMPZYVNIV-UHFFFAOYSA-N 1,4-dihydroisoquinoline Chemical compound C1=CC=C2CC=NCC2=C1 VPKAHUMPZYVNIV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 238000006264 debenzylation reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- KYMUDEQLSUKRGO-UHFFFAOYSA-N C(c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1 Chemical compound C(c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1 KYMUDEQLSUKRGO-UHFFFAOYSA-N 0.000 description 1
- GODRVQNPPALOOT-UHFFFAOYSA-N C1(=CC=CC=C1)[P](CCCC)(C1=CC=CC=C1)C1=CC=CC=C1 Chemical compound C1(=CC=CC=C1)[P](CCCC)(C1=CC=CC=C1)C1=CC=CC=C1 GODRVQNPPALOOT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- UWAXDPWQPGZNIO-UHFFFAOYSA-N benzylsilane Chemical compound [SiH3]CC1=CC=CC=C1 UWAXDPWQPGZNIO-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 238000002564 cardiac stress test Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000035487 diastolic blood pressure Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000006197 hydroboration reaction Methods 0.000 description 1
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 150000007925 phenylethylamine derivatives Chemical class 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000001013 sinoatrial node Anatomy 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000004577 thatch Substances 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Abstract
A process for preparing demethyl coclaurine and its medicinal salt from 2-(3,4-dimethoxyphenyl) ethylamine includes condensation, cyclization, hydrogenation and demethylation. Its advantage is high output rate (37%) increased by 3 times and less environmental pollution.
Description
Technical field
The present invention relates to the new preparation method of demethyl coclaurine and pharmaceutical salts thereof, adopting 2-(3, the 4-Dimethoxyphenyl) ethamine is raw material, goes on foot and makes total recovery 37% through condensation, cyclization, hydrogenation, demethoxylation four.
Background technology
Higenamine hydrochloride (Higenamine Hydrochloride)
Chemical name: 1-(4-hydroxybenzyl)-6.7-dihydroxyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride.
English chemical name: 1-(4-Hydroybenzyl)-6.7-dihydroxy-1,2,3,4-tetrahydroyisoquinoline, hydrochoride
Structural formula:
Higenamine hydrochloride can make heart rate accelerate, and diastolic pressure reduces, and the left ventricular ejection mark increases, and the sinus node conduction function improves; It is good that sinus rhythm is crossed slow curative effect, and myocardial contraction obviously strengthens.
In recent years, the early diagnosis for coronary heart disease more and more is subject to people's attention.Clinically the cardiovascular diseases non-invasive diagnostic is often needed to combine to improve diagnosis rate with load test.But at present assist a ruler in governing a country the medicine that instrument diagnoses uses as drug load some untoward reaction is arranged all, clinical use is not ideal enough.And Higenamine hydrochloride little, the comparatively ideal cardiac stress test medicine that is a kind of side effect.
In the prior art, the production method of Higenamine hydrochloride is to be starting raw material with the Vanillin
After the hydroxybenzyl protection, with the Nitromethane 99Min. reaction, the product lithium aluminium hydride reduction obtains substituted phenyl ethylamine, cyclization after the homoanisic acid acidylate again, reduction, first debenzylation, and back demethoxylation obtains Higenamine hydrochloride at last.Totally eight steps reaction, the yield in five steps of back is 25.7%, total recovery: 12%.(see Acta Pharmaceutica Sinica V16 (12): 931,1981).
The synthetic hydrochloric acid demethyl coclaurine route of reference (Chinese pharmaceutical journal, the 42 volume, first phase P31) report, also be tetrahydroisoquinoline by 6 methoxyl groups, 7 benzyl protections, first debenzylation, back demethoxylation forms.
Summary of the invention
In order to overcome the weak point of prior art, the invention provides a kind of new demethyl coclaurine and the preparation method of pharmaceutical salts thereof.
Chemical equation is as follows:
Specifically, the preparation of demethyl coclaurine and pharmaceutical salts thereof is by following step: (1) N-(3, the 4-dimethoxy)-and the preparation of styroyl-(4-methoxyl group)-phenylacetamide (IV): with 2-(3, the 4-Dimethoxyphenyl) ethamine (II) and 4-methoxyphenylacetic acid (III) condensation.
Be reflected in the suitable organic solvent and carry out, suitable organic solvent is selected from: dimethylbenzene, toluene, dimethyl formyl.
The temperature of reaction is the temperature from the room temperature to the solvent refluxing, and preferred temperature is the temperature of solvent refluxing.
Time time of reaction is from 1-12 hour, preferably 2-10 hour, is more preferably 2.5-3.5 hour.
Isolate the water that generates in the experiment, preferably divide dried up method to use water-and-oil separator.
(2) 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3, the preparation of 4-dihydro-isoquinoline (V):
With N-(3, the 4-dimethoxy)-styroyl-(4-methoxyl group)-phenylacetamide (IV) cyclization.
The ring and in appropriate solvent, carry out, the appropriate solvent of use is toluene or benzene.
Cyclization reagent is phosphorus oxychloride.
The temperature of cyclization is the temperature from the room temperature to the solvent refluxing, preferably the temperature of solvent refluxing.
The time of cyclization is from 1-12 hour, preferably 2-10 hour, is more preferably 2.5-3.5 hour.
(3) (4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline (IV):
With 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline (V) hydrogenation.
Hydrogenation carries out in The suitable solvent, and preferred solvent is an ethanol.
Hydrogenant reagent is selected NaBH for use
4, KBH
4, NaBH (OAC)
3, NaCNBH
3, LiCNBH
3, CNBH
3, Zn/HOAC, (dimethyl methyl is silica-based) carbamate/Ph
3CClO
4, hydroboration benzyl triphenyl phosphorus (BTPPB), benzyl silane/phenylbenzene tindichloride, four boronation butyl triphenyl phosphorus (BTPPTB), NaBH
4/ ACOH, 1-phenyl-1-nitrogen ion-4-azabicyclic [2,2,2] octane tetrahydro-boron (BAAOTB), nickel borides, Decaboron tetradecahydride, HsiCl
3, zinc borohydride, borine-dimethyl sulphide mixture, borine-pyridine mixtures, NaBH
4-Ti (OCHMe
2)
4, NaCNBH
3-TiCl
4, with among the 0.5-1%Ru promoted NiB any.Be preferably sodium borohydride.
The hydrogenant temperature is 20-45 ℃, preferably 25-40 ℃, is more preferably 28-32 ℃.The time of reaction is 5 minutes-5 hours, preferably 15 minutes-3 hours, is more preferably 0.5-1.5 hour.
4, the preparation of demethyl coclaurine (I)
With (4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (VI) demethoxylation.
The reagent of demethoxylation is acid, and reacting employed acid can Hydrogen bromide, in the hydrochloric acid, sulfuric acid, formic acid, citric acid, Dower50 highly acidic resin, methylsulfonic acid, tosic acid any, preferably Hydrogen bromide.
The temperature of reaction is the temperature from the room temperature to the solvent refluxing, preferably the temperature of solvent refluxing.
The time of reaction is 2-10 hour, preferably 4-8 hour, is more preferably 4.5-5.5 hour.
Use alkali neutralization reaction liquid to PH7.5-8.5 after reacting completely, preferably use ammoniacal liquor to neutralize.
Separate out post precipitation, filter solid demethyl coclaurine (I).
" pharmaceutical salts " of the present invention refers to the pharmaceutically acceptable acid-salt of demethyl coclaurine.The example of pharmaceutical salts comprises, but is not limited to and the nontoxic salt of inorganic or organic acid addition.For example, this traditional nontoxic salt comprises, is not limited to acetate, 2-acetoxyl group M-nitro benzoic acid, hydrochloric acid, lipid acid, citric acid, preferably hydrochloric acid.Pharmacy acceptable salt of the present invention can be synthetic by conventional chemical reaction, for example, by free demethyl coclaurine and stoichiometric suitable acid-respons, in water or in the organic solvent, or both mixtures, (non-aqueous media such as ether, ethyl acetate, ethanol, Virahol, or second cyanogen is preferred), or by free demethyl coclaurine and excessive needed shape salifiable inorganic or organic acid or alkali reaction, in The suitable solvent or in the various admixture solvent.Example adding distil water and concentrated hydrochloric acid prepare Higenamine hydrochloride.The tabulation of suitable salt can be at Remington ' s pharmaceutical science, and 17 editions, Mack publishing company, Easton, Pa., 1985, p.1418, to find among the et al., wherein all being disclosed in here quoted as a reference.
The technology convenient and efficient of synthetic demethyl coclaurine of the present invention and hydrochloride thereof.By 3,4-dimethoxy-phenylethylamine and homoanisic acid condensation, cyclization, reduction, the demethoxylation four-step reaction obtains demethyl coclaurine and pharmaceutical salts thereof, and total recovery reaches 37%.Compare with prior art, adopt cheaply 3, the 4-dimethoxy-phenylethylamine is a raw material, has saved lithium aluminum hydride, and total recovery improves 3 times, compares with the yields in five steps of back in the prior art from 25.7% and brings up to 37%, improves near 50%.The present invention has reduced cost, simplified operation, reduced reaction in the three wastes, reduced environmental pollution.
Embodiment
1, the preparation of N-(3, the 4-dimethoxy)-styroyl-(4-methoxyl group)-phenylacetamide (IV):
With 2-(3, the 4-Dimethoxyphenyl) ethamine (II) 28g (0.15M), 4-methoxyphenylacetic acid (III) 25.6g (0.15M) and dimethylbenzene 260ml add in the there-necked flask, add a little water-and-oil separator, stirring and refluxing 3 hours, tell the water of generation, stop, cooling off, put refrigerator, 2 hours after-filtration, wash with a small amount of dimethylbenzene, get white crystals product (IV) 50g, productive rate 98.4%, molten some 108-110 ℃.
2,1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3, the preparation of 4-dihydro-isoquinoline (V):
With compound (IV) 15g (0.0456M), toluene 80ml and phosphorus oxychloride 15g, stirring and refluxing 3 little elbows.After cold, pour in the 200ml frozen water, refrigerator is placed and to be spent the night, filters, precipitate and wash with water to neutrality, after filter is dried, must the about 16g of thick product (V), and mp 120-130 ℃.
3,1-(4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3, the preparation of 4-tetrahydroisoquinoline (IV):
Thick product 16g of compound (V) and 95% ethanol 150ml are added in the bottle, stir, gradation adds sodium borohydride 2.5g, finish, water-bath is heated to about 30 ℃, stirs underpressure distillation then 1 hour, steam most of ethanol to the greatest extent, residue adds water 200ml dissolving, aqueous solution dichloromethane extraction three times, about at every turn 80ml.Extracting solution merges, and steams solvent residue oily matter to the greatest extent, is the thick product of compound (IV), the 10.3g that weighs, yield 72%, mp 76-78 ℃.
4, the preparation of Higenamine hydrochloride (I)
The thick product 10.3g and the 45% Hydrogen bromide 200ml of compound (VI) are added in the bottle, and stirring and refluxing 5 hours is steamed solvent to the greatest extent then.Residue adds water 200ml dissolving, filters, and filtrate adds ammoniacal liquor and is neutralized to PH8, separates out precipitation, filter solid, adding distil water 150ml and concentrated hydrochloric acid 4ml.It is acid that solution is, and heating for dissolving adds gac 2g, refluxed 10 minutes, and filtered while hot, filtrate is placed refrigerator overnight, separates out white solid, filters, and gets highly finished product 6g of thatch.
Highly finished product 6g adding distil water 90ml and the gac 1g recrystallization second time gets white highly finished product (I) 5.3g, yield 52.5% for the first time.
Fusing point 260-262 ℃
Total recovery reaches 37%.
Claims (9)
1, the preparation method of a kind of demethyl coclaurine and pharmaceutical salts thereof is characterized in that, comprises the steps:
(1) 2-(3, the 4-Dimethoxyphenyl) ethamine (II) and 4-methoxyphenylacetic acid (III) condensation prepared N-(3, the 4-dimethoxy)-styroyl-(4-methoxyl group)-phenylacetamide (IV);
(2) N-(3, the 4-dimethoxy)-styroyl-(4-methoxyl group)-phenylacetamide (IV) cyclization is prepared 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline (V);
(3) with 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline (V) hydro-reduction prepares 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (VI);
(4) with 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (VI) demethoxylation makes demethyl coclaurine (I), selectable again with sour combination.
According to the preparation method of claim 1, it is characterized in that 2, the water that condensation produces in the step (1) separates with water-and-oil separator.
3, according to the preparation method of claim 1, it is characterized in that the phosphorus oxychloride that cyclization is used in the step (2).
According to the preparation method of claim 1, it is characterized in that 4, what step (3) hydrogenation was used is sodium borohydride.
According to the preparation method of claim 1, it is characterized in that 5, the used reagent of demethoxylation is Hydrogen bromide in the step (4).
According to the preparation method of claim 1, it is characterized in that 6, described pharmaceutical salts is a hydrochloride.
7, compound N-(3, the 4-dimethoxy)-styroyl-(4-methoxyl group)-phenylacetamide (IV).
8, compound 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-3,4-dihydro-isoquinoline (V).
9, compound 1-(4-methoxyl group-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (VI).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310101649 CN1266135C (en) | 2003-10-27 | 2003-10-27 | Method for preparing new demethyl conclaurine and medinal salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310101649 CN1266135C (en) | 2003-10-27 | 2003-10-27 | Method for preparing new demethyl conclaurine and medinal salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1539823A true CN1539823A (en) | 2004-10-27 |
| CN1266135C CN1266135C (en) | 2006-07-26 |
Family
ID=34333080
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200310101649 Expired - Lifetime CN1266135C (en) | 2003-10-27 | 2003-10-27 | Method for preparing new demethyl conclaurine and medinal salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1266135C (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351338A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Simple preparation process of higenamine hydrochloride |
| CN103554022A (en) * | 2013-10-31 | 2014-02-05 | 苏州永健生物医药有限公司 | Synthetic method of higenamine hydrochloride |
| CN103626703A (en) * | 2013-11-18 | 2014-03-12 | 珠海润都制药股份有限公司 | Preparation method of chiral higenamine and derivatives of chiral higenamine |
| CN112409257A (en) * | 2020-11-30 | 2021-02-26 | 天津阿尔塔科技有限公司 | Preparation method of deuterium-labeled higenamine stable isotope compound |
| CN115260094A (en) * | 2022-06-16 | 2022-11-01 | 珠海润都制药股份有限公司 | Novel synthetic method of higenamine hydrochloride |
| CN115536584A (en) * | 2022-11-02 | 2022-12-30 | 珠海润都制药股份有限公司 | Synthetic method of higenamine hydrochloride |
-
2003
- 2003-10-27 CN CN 200310101649 patent/CN1266135C/en not_active Expired - Lifetime
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103351338A (en) * | 2013-06-17 | 2013-10-16 | 张家港威胜生物医药有限公司 | Simple preparation process of higenamine hydrochloride |
| CN103554022A (en) * | 2013-10-31 | 2014-02-05 | 苏州永健生物医药有限公司 | Synthetic method of higenamine hydrochloride |
| CN103554022B (en) * | 2013-10-31 | 2015-12-30 | 苏州永健生物医药有限公司 | A kind of synthetic method of Higenamine hydrochloride |
| CN103626703A (en) * | 2013-11-18 | 2014-03-12 | 珠海润都制药股份有限公司 | Preparation method of chiral higenamine and derivatives of chiral higenamine |
| CN103626703B (en) * | 2013-11-18 | 2015-11-11 | 珠海润都制药股份有限公司 | The preparation method of chirality demethyl coclaurine and derivative thereof |
| CN112409257A (en) * | 2020-11-30 | 2021-02-26 | 天津阿尔塔科技有限公司 | Preparation method of deuterium-labeled higenamine stable isotope compound |
| CN115260094A (en) * | 2022-06-16 | 2022-11-01 | 珠海润都制药股份有限公司 | Novel synthetic method of higenamine hydrochloride |
| CN115260094B (en) * | 2022-06-16 | 2024-04-05 | 珠海润都制药股份有限公司 | New method for synthesizing norlinderane hydrochloride |
| CN115536584A (en) * | 2022-11-02 | 2022-12-30 | 珠海润都制药股份有限公司 | Synthetic method of higenamine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1266135C (en) | 2006-07-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101717392A (en) | Method for preparing rotigotine and derivative thereof | |
| CN111051280A (en) | Process for producing pyrrolidine compound | |
| EP0763010A1 (en) | Enantioselective preparation of optically pure albuterol | |
| CN1266135C (en) | Method for preparing new demethyl conclaurine and medinal salt | |
| CN1705664A (en) | Process for the preparation of (S,S)-cis-2-benzhydryl-3-benzylaminoquinuclidine | |
| JPH09216857A (en) | Production of antipode of o-demethyltramadol | |
| DE2354002A1 (en) | NEW N- (METHOXYMETHYL-FURYLMETHYL) 6,7-BENZOMORPHANES AND MORPHINANES, THEIR ACID-ADDITION SALTS, THEIR USE AS A MEDICINAL PRODUCTS AND METHOD FOR THE PREPARATION | |
| CN103664677A (en) | Asymmetric synthesis method of (R,R)-formoterol tartrate | |
| CN1544427A (en) | Luteolin semi-synthesis method | |
| CA1077488A (en) | Phenylethanolamines | |
| Banitt et al. | Resolution of flecainide acetate, N-(2-piperidylmethyl)-2, 5-bis (2, 2, 2-trifluoroethoxy) benzamide acetate, and antiarrhythmic properties of the enantiomers | |
| CN101684074A (en) | Unsymmetrical hydrogen transfer synthetic method of (R)-salmeterol | |
| IE47721B1 (en) | New derivatives of 1-azabicyclo(2.2.2)octane,process for their preparation,their use as medicaments and intermediates for their preparation | |
| CN107778234B (en) | Preparation method of neuromuscular blocker intermediate | |
| CN102229538A (en) | Method for synthesizing dapoxetine | |
| CN114890948A (en) | Preparation method of neuromuscular blocker intermediate | |
| CN1130199C (en) | A improved method of synthesis for 6,9-bis[(2-aminoethyl)amino] benzo[g] isoquinoline-5,10-dione and its dimaleate salt | |
| CN101580460B (en) | Synthesis method of 3, 4-dihydroxy phenylethanol | |
| CN100427460C (en) | Method for synthesis of L-norvaline | |
| CN104086486B (en) | The preparation method of a kind of Dimemorfan phosphate | |
| CN1488622A (en) | Method for preparing memantine hydrochloride | |
| CN1166660C (en) | Process for preparing N-methyl piperethanamine salt | |
| CN105884625A (en) | Synthesis method of R-salmeterol | |
| CN101544616B (en) | Novel method for synthesizing dyclonine hydrochloride | |
| CN1396162A (en) | Xanthiphenyl ketamine or its salt and its preparing process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: ZHUHAI RUNDU MINTONG PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: MINTONG PHARMACEUTICAL FACTORY, ZHUHAI SPECIAL ECONOMIC ZONE |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100050 NO.1, XIANNONGTAN STREET, XUANWU DISTRICT, BEIJING TO: 100050 NO.1, XIANNONGTAN STREET, XUANWU DISTRICT, BEIJING, CHINA |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20110105 Address after: 100050 Beijing city Chinese Xuanwu District Xiannongtan Street No. 1 Co-patentee after: Zhuhai Rundu Mintong Pharmaceutical Co.,Ltd. Patentee after: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES Address before: 100050 Beijing city Xuanwu District Xiannongtan Street No. 1 Co-patentee before: Mintong Pharmaceutical Factory, Zhuhai Special Economic Zone Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| C56 | Change in the name or address of the patentee | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 100050 Beijing city Chinese Xuanwu District Xiannongtan Street No. 1 Co-patentee after: ZHUHAI RUNDU PHARMACEUTICAL Co.,Ltd. Patentee after: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES Address before: 100050 Beijing city Chinese Xuanwu District Xiannongtan Street No. 1 Co-patentee before: Zhuhai Rundu Mintong Pharmaceutical Co.,Ltd. Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| ASS | Succession or assignment of patent right |
Owner name: ZHUHAI RUNDU PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: PHARMACOLOGY INST. OF CAMS Effective date: 20111103 Free format text: FORMER OWNER: ZHUHAI RUNDU PHARMACEUTICAL CO., LTD. |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 100050 XUANWU, BEIJING TO: 519040 ZHUHAI, GUANGDONG PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20111103 Address after: 519040 Guangdong province Zhuhai Sanzao airport Jinwan District Road No. 6 Patentee after: ZHUHAI RUNDU PHARMACEUTICAL Co.,Ltd. Address before: 100050 Beijing city Chinese Xuanwu District Xiannongtan Street No. 1 Co-patentee before: ZHUHAI RUNDU PHARMACEUTICAL Co.,Ltd. Patentee before: INSTITUTE OF MATARIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES |
|
| CX01 | Expiry of patent term |
Granted publication date: 20060726 |
|
| CX01 | Expiry of patent term |