CN101906097A - 1,3-dioxane compounds as well as synthesizing method and medical application thereof - Google Patents
1,3-dioxane compounds as well as synthesizing method and medical application thereof Download PDFInfo
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- CN101906097A CN101906097A CN2009100851559A CN200910085155A CN101906097A CN 101906097 A CN101906097 A CN 101906097A CN 2009100851559 A CN2009100851559 A CN 2009100851559A CN 200910085155 A CN200910085155 A CN 200910085155A CN 101906097 A CN101906097 A CN 101906097A
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- Prior art keywords
- tetrahydroisoquinoline
- serine
- formyl radical
- preparation
- dioxane
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- 238000000034 method Methods 0.000 title claims abstract description 16
- 150000000093 1,3-dioxanes Chemical class 0.000 title abstract description 4
- 230000002194 synthesizing effect Effects 0.000 title abstract 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 15
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 11
- 229960004676 antithrombotic agent Drugs 0.000 claims abstract description 5
- 238000002360 preparation method Methods 0.000 claims description 64
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 229960001153 serine Drugs 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- -1 acyl Serine Chemical compound 0.000 claims description 16
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 16
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 12
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 12
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 6
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 claims description 6
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- BNHQWMNGVIMKKZ-UHFFFAOYSA-N tert-butyl 3,4,4a,5-tetrahydro-1h-isoquinoline-2-carboxylate Chemical compound C1C=CC=C2CN(C(=O)OC(C)(C)C)CCC21 BNHQWMNGVIMKKZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960005190 phenylalanine Drugs 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 59
- 208000007536 Thrombosis Diseases 0.000 abstract description 5
- 150000001413 amino acids Chemical class 0.000 abstract description 3
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 abstract 1
- 238000013329 compounding Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 37
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 29
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 20
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000002526 effect on cardiovascular system Effects 0.000 description 4
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- BWKMGYQJPOAASG-VIFPVBQESA-N (3s)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN[C@H](C(=O)O)CC2=C1 BWKMGYQJPOAASG-VIFPVBQESA-N 0.000 description 3
- HFPVZPNLMJDJFB-LBPRGKRZSA-N (3s)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-LBPRGKRZSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 description 3
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
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- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 1
- OQGAELAJEGGNKG-QHCPKHFHSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-oxo-4-phenylmethoxybutanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C(=O)OCC1=CC=CC=C1 OQGAELAJEGGNKG-QHCPKHFHSA-N 0.000 description 1
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- ZPGDWQNBZYOZTI-UHFFFAOYSA-N 1-(9h-fluoren-9-ylmethoxycarbonyl)pyrrolidine-2-carboxylic acid Chemical compound OC(=O)C1CCCN1C(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21 ZPGDWQNBZYOZTI-UHFFFAOYSA-N 0.000 description 1
- QDGAVODICPCDMU-UHFFFAOYSA-N 2-amino-3-[3-[bis(2-chloroethyl)amino]phenyl]propanoic acid Chemical compound OC(=O)C(N)CC1=CC=CC(N(CCCl)CCCl)=C1 QDGAVODICPCDMU-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- 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 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
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- NDBQJIBNNUJNHA-DFWYDOINSA-N methyl (2s)-2-amino-3-hydroxypropanoate;hydrochloride Chemical class Cl.COC(=O)[C@@H](N)CO NDBQJIBNNUJNHA-DFWYDOINSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses 1,3-dioxane compounds as well as a synthesizing method and medical application thereof. The synthesizing method comprises the following steps of: compounding tetrahydroisoquinoline and 1,3-dioxane, and then modifying the N end of the tetrahydroisoquinoline by using 20 kinds of endogenous amino acid to obtain the 1,3-dioxane compounds with excellent antithrombotic activities, which are evaluated by adopting a rat thrombus model. The experimental results indicate that the compounds all have excellent antithrombotic activities and can be clinically used as antithrombotic agents.
Description
Technical field
The present invention relates to six lopps compounds, relate in particular to and have 1 of antithrombotic acitivity, the 3-dioxanes compounds, the invention still further relates to this 1, the synthetic method of 3-dioxanes compounds and they belong to biomedicine field as the application of antithrombotic agent.
Background technology
The M ﹠ M of cardiovascular and cerebrovascular diseases day by day rises at present.The major cause that causes cardiovascular and cerebrovascular diseases is to form thrombus in the blood vessel.Thrombocyte plays a part very crucial in the thrombotic process.Anticoagulant, and then suppress the important step that thrombosis has become the various cardiovascular disordeies of prevention.So the research to medicament for resisting platelet aggregation also receives publicity day by day.
Thromboxane (TXA
2) be arachidonic meta-bolites, be a kind of strong platelet aggregating agent, many cardiovascular disordeies and TXA
2Excessive generation relevant, so thromboxane synthetase inhibitor and thromboxane receptor antagonist be the focus of research at present, especially based on 1, the research of 3-dioxane parent nucleus.And it is reported that tetrahydroisoquinoline has good platelet aggregation inhibitory activity, the contriver recognizes tetrahydroisoquinoline and 1, and the combination of 3-dioxane is terminal modified to tetrahydroisoquinoline N with 20 kinds of endogenous amino acid, the antithrombotic reagent that can obtain, so the contriver proposes the present invention.
Summary of the invention
One of the object of the invention is with tetrahydroisoquinoline and 1, and the combination of 3-dioxane is modified tetrahydroisoquinoline N end with 20 kinds of endogenous amino acid, obtains a class and has 1 of outstanding antithrombotic acitivity, the 3-dioxanes compounds;
Two of the object of the invention provides a kind of synthetic above-mentioned 1, the method for 3-dioxanes compounds;
Three of the object of the invention provides above-mentioned, a kind of purposes of 3-dioxanes compounds in medical science.
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
Have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
General formula I
Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Another object of the present invention provides a kind of above-mentioned 1 of antithrombotic acitivity that has for preparing, the method for 3-dioxanes compounds, and this method may further comprise the steps:
(1) preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol; (3) with 1,2,3, the two pure and mild paranitrobenzaldehyde condensations of 4-tetrahydroisoquinoline acyl Serine generate 5-[1, and 2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (4) with 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate 5-[Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (5) 5-(Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical)-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis, promptly; Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
Wherein, described N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol can prepare with reference to following method:
(1) at SOCl
2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine into 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety; (3) at (Boc)
2With 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety changed N-tertbutyloxycarbonyl tetrahydroisoquinoline under O and NaOH existed; (4) L-serine methylester and the condensation of N-tertbutyloxycarbonyl tetrahydroisoquinoline generate N-[(3S in the presence of DCC, HOBt)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-the L-serine methylester.
Described 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol can prepare with reference to following method:
(1) at NaBH
4Following to N-t-butoxycarbonyl amino acyl-1,2,3 with the THF existence, the reduction of 4-tetrahydroisoquinoline acyl serine methylester generates N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) in the presence of hydrogenchloride-THF with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydroisoquinoline acyl silk glycol generates 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol.
Estimate the antithrombotic acitivity of compound of the present invention on the rat anti thrombus model, test-results shows that chemical combination of the present invention has outstanding antithrombotic acitivity, can be used as antithrombotic agent and uses.
Another purpose of the present invention provides the medicinal compositions of the above-mentioned general formula compound of a kind of the present invention of containing, and this medicinal compositions is gone up effective dose by treatment The compounds of this invention is with pharmaceutically acceptable excipient or assist and add agent and form; That is: with the The compounds of this invention of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, by the formulation method of this area routine it is prepared into any one appropriate drug composition.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
Description of drawings
The synthetic route chart of Fig. 1 The compounds of this invention; I) formaldehyde and concentrated hydrochloric acid, 80 ℃ of oil bath condensing refluxes; Ii) (Boc)
2O, the NaOH ice bath; Iii) SOCl
2, CH
3The OH cryosel is bathed iv) Ser-OMe, DCC, HoBt, NMM ice bath; V) NaBH
4, THF; Vi) vii) paranitrobenzaldehyde of 4N HCl/THF, BF
3Et
2O, CH
3The CN ice bath; Viii) Fmoc-AA, DCC, HoBt, NMM ice bath; Wherein AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr; Ix) NaOH/CH
3OH, CH
2Cl
2, ice bath; AA represents H, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys, Tyr.
Embodiment
In order further to set forth the present invention, provide a series of examples below.These examples are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
In 4.0g (24.2mmol) L-phenylalanine, dropwise add 21.6ml formaldehyde earlier, dropwise add 36ml 35% concentrated hydrochloric acid again.The suspension oil bath that obtains is heated to 2 two hours phenylalanines of 80-90 ℃ of stirring and dissolves fully, reacts after 2.5 hours, begins to have colourless precipitation to generate, and reacts TLC (CHCl 7 hours
3/ CH
3OH=5/1) show that the L-phenylalanine disappears, suction filtration gets the 4.2g colorless solid, the gained colorless solid is joined in the 86ml ethanol (80%) 80 ℃ of oil baths heating 9 hours, dissolve to colorless solid, be cooled to room temperature, slowly drip 1ml (1.376g potassium hydroxide is dissolved in 1ml distilled water) potassium hydroxide solution, have colourless precipitation to separate out, filter 4.02g (94%) title compound, be colorless solid.MP:302.1-302.5 ℃, [α]
D 25=-68 (c 1 methyl alcohol); ESI-MS (m/z) 176[M-1]
-
The following 2.49g of ice bath (62.15mmol) sodium hydroxide dissolves in 62.2ml water, adds 10g (56.49mmol) then (3S)-1,2,3, and 4-tetrahydroisoquinoline-3-carboxylic acid is made suspension.With 40ml tetrahydrofuran (THF) dissolving 14.8g (67.8mmol) (Boc)
2O adds in the suspension.Reaction mixture stirred 48 hours, the solution becomes clarification, and TLC (ethyl acetate/petroleum ether: 1: 3) shows (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid disappears, and stops reaction.The reaction mixture concentrating under reduced pressure is removed tetrahydrofuran (THF), the oily matter acetic acid ethyl dissolution that obtains.The solution that obtains is used 5%KHSO successively
4Wash with the saturated NaCl aqueous solution.Organic layer is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression, the oily matter that obtains stirred 24 hours with ethyl acetate/petroleum ether (1: 10), and the colorless solid that obtains filters, and obtains 12.5g (79.9%) title compound.ESI-MS (m/z) 278.2[M+1]
+, [α]
D 25=-6.78 (c 1 methyl alcohol);
The 50ml anhydrous methanol is dripping thionyl chloride 3.75ml (0.050mol) under ice bath, adds L-Serine 5g (0.042mol) behind the 30min, and stirring at room 24h, TLC monitor to raw material disappearance termination reaction.Water pump is taken the intact sulfur oxychloride SOCl of unreacted away
2And HCl, with sherwood oil grind repeatedly white solid 7.34g (productive rate 99%), Mp:161 ℃-162 ℃
Embodiment 4 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-serine methylester (3)
Ice bath down with anhydrous THF with 5.54g (20mmol) (3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid dissolving, add 2.8g (21mmol) N-hydroxy benzo triazole (HOBt), the dissolving back adds 4.9g (24mmol) dicyclohexyl carbonyl diimine (DCC), obtains reaction solution (I).2.6g (16.7mmol) HClSer-OMe is suspended among the anhydrous THF, adds N-methylmorpholine (NMM) and transfer pH value 8～9, get reaction solution (II).(I) added in (II), and stirring at room 12h, TLC (petrol ether/ethyl acetate, 3: 1) show that HClSer-OMe disappears.Leach dicyclohexylurea (DCU) (DCU), filtrate decompression is concentrated into dried, residue 80ml acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, 5%KHSO
4The aqueous solution, the saturated NaCl aqueous solution, saturated NaHCO
3The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior.The ethyl acetate layer anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate 5.68g (90%) title compound, be colorless solid
Embodiment 5 preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (4)
With 5 dissolvings of 0.378g (1mmol) compound, ice bath adds 0.152g (4mmol) NaBH following minute three times with THF
4, behind the reaction 12h, TLC (CHCl
3/ CH
3OH, 10: 1) show that raw material disappears.With the HCl aqueous solution adjust pH 5-6 of 2N, concentrating under reduced pressure is removed THF, residue EtOAc/H under the ice bath vigorous stirring
2O dissolving, separatory, water layer EtOAc extracting twice, the ester layer is with 5% KHSO
4The aqueous solution, the saturated NaCl aqueous solution are respectively given a baby a bath on the third day after its birth inferior, ester layer anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate 0.210g (60%) title compound, be colorless solid [α]
D 25=-8.67 (c 0.65CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 351[M+H]
+
Embodiment 6 preparation N-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol (5)
With a small amount of anhydrous THF dissolving of 0.210g (0.6mmol) compound 4 usefulness, ice bath drips 2ml 4N HCl/THF solution down, stirring reaction, and behind about 2h, TLC (CHCl
3/ CH
3OH, 10: 1) show that raw material disappears, in reaction solution, pour a large amount of ether into, there is colorless solid to separate out, leave standstill, inclining supernatant liquor, and solid adds diethyl ether and takes out three times, gets oily matter, is directly used in the next step.ESI-MS(m/z)：251[M+H]
+
Embodiment 7 preparation 5-[(3S)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (6)
Add the 2ml acetonitrile and suspend in 0.287g (1mmol) compound 5, add 0.302g (2mmol) paranitrobenzaldehyde, ice bath stirs down, slowly drips 0.25ml BF
3Et
2O, reaction solution becomes clarification, and along with reaction, reaction solution becomes the jelly shape.TLC (CHCl
3/ CH
3OH, 10: 1) monitoring, initial point does not have colour developing, filters, and filter cake is washed till white with EtOAc, and filter cake is transferred in the 100ml eggplant bottle, adds saturated NaHCO
3The aqueous solution, adjust pH to 8 stirs half an hour, filters, and gets title compound, colorless solid 0.214g (56%); Mp:217-217.4 ℃; [α]
D 25=-53.23; (c 0.65CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 384.2[M+H]
+
Embodiment 8 preparation 5-[(3S)-and N-Fmoc-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7a)
Ice bath dissolves 0.289g (0.85mmol) Fmoc-Val with anhydrous THF down, add 0.1g (0.74mmol) N-hydroxy benzo triazole (HOBt), the dissolving back adds 0.175g (0.85mmol) dicyclohexyl carbonyl diimine (DCC) and obtains reaction solution (I), 0.272g (0.71mmol) compound 6 is suspended in the dry DMF, add N-methylmorpholine (NMM) and transfer pH value 8～9, get reaction solution (II).(I) added in (II) stirring at room 24h, TLC (CH
2Cl
2/ CH
3OH, 20: 1) show that compound 8 disappears.Leach dicyclohexylurea (DCU) (DCU), filtrate dries up, residue 10ml acetic acid ethyl dissolution.Filter, the solution that obtains is used 5%NaHCO successively
3The aqueous solution, the saturated NaCl aqueous solution, it is inferior respectively to give a baby a bath on the third day after its birth.The ethyl acetate layer anhydrous Na
2SO
4Drying, filtration, filtrate decompression concentrate, through silica gel column chromatography obtain 0.3g (60%) title compound (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), be colorless solid; Mp:108.2-109.6 ℃; [α]
D 25=-67.33 (C 0.65; CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 727.3[M+Na]
+
Embodiment 9 preparation 5-[(3S)-and N-Fmoc-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7b)
According to the operation of preparation 7a, get 0.312g (43%) title compound, (CH from 0.414g (1.23mmol) Fmoc-Leu and 0.392g (1.02mmol) compound 6
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp：118.2-120.0℃[α]
D 25＝-63.88(C?0.55CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：719.2[M+H]
+
Embodiment 10 preparation 5-[(3S)-and N-Fmoc-Ile-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7c)
According to the operation of preparation 7a, 0.221g (0.63mmol) Fmoc-Ile and 0.2g (0.52mmol) compound 6 get 0.242g (65%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp：101.9-102.5°C；[α]
D 25＝-56.10(C?0.7?CH
2Cl
2/CH
3O?1∶1?V/V)；ESI-MS(m/z)719.2[M+H]
+
Embodiment 11 preparation 5-[(3S)-and N-Fmoc-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7d)
According to the operation of preparation 7a, 0.279g (0.94mmol) Fmoc-Gly and 0.3g (0.78mmol) compound 6 get 0.3g (58%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.20), colorless solid.Mp：128.3-128.9℃[α]
D 25＝-64.67(C?0.2CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：663.2[M+H]
+，685.2[M+Na]
+
Embodiment 12 preparation 5-[(3S)-and N-Fmoc-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7e)
According to the operation of preparation 7a, 0.298g (0.95mmol) Fmoc-Ala-OH and 0.306g (0.80mmol) compound 6 get 0.3g (55%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid; Mp169.9-171.8 ℃ [α]
D 25=-52.53 (C 0.5CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 699[M+Na]
+
Embodiment 13 preparation 5-[(3S)-and N-Fmoc-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7f)
According to the operation of preparation 7a, 0.511g (1.20mol) Fmoc-Trp and 0.383g (1mmol) compound 6 get 0.352g (45%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.22), yellow solid.Mp：129.4-130.5℃[α]
D 25＝-16.29(C?0.8CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：792[M+H]
+；814.5[M+Na]
+
Embodiment 14 preparation 5-[(3S)-and N-Fmoc-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7g)
According to the operation of preparation 7a, 0.260g (0.76mmol) Fmoc-Thr and 0.244g (0.63mmol) compound 6 get 0.204g (46%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.18), colorless solid.Mp：98.5-100.1℃；[α]
D 25＝-40.85(C?0.9CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：729.5[M+Na]
+
Embodiment 15 preparation 5-[(3S)-and N-Fmoc-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7h)
According to the operation of preparation 7a, 0.387g (1.04mmol) Fmoc-Met and 0.333g (0.87mmol) compound 6 get 0.278g (43%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.23), colorless solid.Mp：195.2-196.2℃；[α]
D 25＝-59.95(C?0.7CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：759.6[M+Na]
+。
Embodiment 16 preparation 5-[(3S)-and N-Fmoc-Asp (OBzl)-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7i)
According to the operation of preparation 7a, 0.62g (1.39mmol) Fmoc-Asp (OBzl) and 0.445g (1.16mmol) compound 6 get 0.48g (51%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.25), colorless solid.Mp：102.4-103.8℃；[α]
D 25＝-20.88(C?0.9CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：833.8[M+Na]
+
Embodiment 17 preparation 5-[(3S)-and N-Fmoc-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7j)
According to the operation of preparation 7a, 0.351g (1.04mmol) Fmoc-Pro and 0.333g (0.87mmol) compound 6 get 0.353g (58%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.21), colorless solid.Mp：116.7-118.4℃；[α]
D 25＝-55.70(C?1?CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：725.5[M+H]
+
Embodiment 18 preparation 5-[(3S)-and N-Fmoc-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (7k)
According to the operation of preparation 7a, 0.403g (1.04mmol) Fmoc-Phe and 0.333g (0.87mmol) compound 6 get 0.340g (52%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.24), colorless solid.Mp：186-186.8℃；[α]
D 25＝-51.68(C?1.05CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：775.4[M+23]
+
Embodiment 19 preparation 5-[(3S)-N-(Fmoc)
2-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7l)
According to the operation of preparation 7a, 0.708g (1.20mmol) (Fmoc)
2-Lys and 0.383g (1.00mmol) compound 6 gets 0.45g (47%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid.Mp：107.8-108.9℃；[α]
D 25＝-33.76(C?0.7CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：978.4[M+23]
+
Embodiment 20 preparation 5-[(3S)-and N-Fmoc-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (7m)
According to the operation of preparation 7b, 0.241g (0.6mmol) Fmoc-Tyr and 0.191g (0.5mmol) compound 6 get 0.17g (44%) title compound, (CH
2Cl
2: CH
3OH=20: 1, Rf=0.26), colorless solid.Mp：128.3-130.2℃；[α]
D 25＝-43.71(C?0.35CH2Cl2/CH3OH?1∶1?V/V)；ESI-MS(m/z)：791.5[M+Na]
+
Embodiment 21 preparation 5-[(3S)-and N-Val-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8a)
With a small amount of CH of 0.25g 7a
2Cl
2Dissolving.Drip the NaOH/CH of 0.25N
3OH solution, pH value about 11, ice bath is reaction 6h down, and the TLC detection reaction is complete, (CH
2Cl
2: CH
3OH=20: 1), be evaporated to driedly, solid is worn away three times with ether, again with a small amount of washing, title compound 0.12g (71%); Mp:89.2-91.0 ℃; [α]
D 25=-21.24 (C 0.75CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 483[M+H]
+
Embodiment 22 preparation 5-[(3S)-and N-Leu-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl 1,3-dioxane (8b)
Operation according to preparation 8a gets 0.172g (83%) title compound (colorless solid) from 0.300g (0.41mmol) 7b.Mp：100.8-101.6℃；[α]
D 25＝-47.00(C?0.8CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)497.5[M+H]
+
Embodiment 23 preparation 5-[(3S)-and N-Ile-1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8c)
Operation according to preparation 8a gets 0.120g (87%) title compound (colorless solid) from 0.200g (0.27mmol) 7c.Mp：101.1-103.1℃；[α]
D 25＝-43.92(C?0.65CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：497.3[M+H]
+
Embodiment 24 preparation 5-[(3S)-and N-Gly-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8d)
Operation according to preparation 8a gets 0.151g (91%) title compound (colorless solid) from 0.250g (0.38mmol) 7d.Mp：126.9-129.0℃[α]
D 25＝-18.2(C?0.5CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：441.3[M+H]
+；463.3[M+Na]
+
Embodiment 25 preparation 5-[(3S)-and N-Ala-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8e)
Operation according to preparation 8a gets 0.156g (90%) title compound (colorless solid) from 0.260g (0.38mmol) 7e.Mp：87.5-89.2℃；[α]
D 25＝-45.94(C?0.55CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：455.4[M+H]
+
Embodiment 26 preparation 5-[(3S)-and N-Trp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8f)
Operation according to preparation 8a gets 0.152g (79%) title compound (colorless solid) from 0.300g (0.38mmol) 7f.Mp：128.5-130.2℃；[α]
D 25＝8.48(C?0.9CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：570.4[M+H]
+
Embodiment 27 preparation 5-[(3S)-and N-Thr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8g)
Operation according to preparation 8a gets 0.08g (78%) title compound (colorless solid) from 0.150g (0.21mmol) 7g.Mp：142-144℃；[α]
D 25＝-42.57(C?0.8CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：485.2[M+H]
+
Embodiment 28 preparation 5-[(3S)-and N-Met-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8h)
Operation according to preparation 8a gets 0.124g (81%) title compound (colorless solid) from 0.220g (0.30mmol) 7h.Mp：111.8-113.2℃；[α]
D 25＝-42.00(C?0.5CH
2Cl
2/CH
3OH?1∶1V/V)；ESI-MS?m/z)：515.3[M+H]
+
Embodiment 29 preparation 5-[(3S)-and N-Asp-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8i)
Use the NaOH/CH of 0.5N according to the operation of preparation 8a
3OH suspension solution adjust pH 12, after reacting completely, under the vigorous stirring, the KHSO with 5%
4The slow adjust pH 5-6 of solution revolves CH
2Cl
2/ CH
3OH, residue adds less water, CH
2Cl
2Extract anhydrous Na three times
2SO
4Drying is filtered, and is spin-dried for, and ether is given a baby a bath on the third day after its birth inferior, gets 0.170g (70%) title compound (faint yellow solid) from 0.400g (0.49mmol) 7i.Mp：90.0-91.6℃[α]
D 25＝-80.87(C0.5CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：513.4[M+15]
+
Embodiment 30 preparation 5-[(3S)-and N-Pro-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8j)
Operation according to preparation 8a gets 0.177g (90%) title compound (colorless solid) from 0.290g (0.41mmol) 7j.Mp：188.1-189.0℃；[α]
D 25＝-73.33(C?0.6CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：481.4[M+H]
+
Embodiment 31 preparation 5-[(3S)-and N-Phe-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8k)
Operation according to preparation 8a gets 0.162g (92%) title compound (colorless solid) from 0.250g (0.33mmol) 7k.Mp：154.0-155.8℃；[α]
D 25＝-16.12(C?0.55CH
2Cl
2/CH
3OH?1∶1?V/V)ESI-MS(m/z)：531.6[M+H]
+；553.6[M+Na]
+
Embodiment 32 preparation 5-[(3S) N-Lys-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8l)
Operation according to preparation 8a gets 0.190g (90%) title compound (colorless solid) from 0.400g (0.42mmol) 7l; Mp:129.3-131.1 ℃; [α]
D 25=-45.47 (C 0.65CH
2Cl
2/ CH
31: 1 V/V of OH); ESI-MS (m/z): 512.3[M+H]
+
Embodiment 33 preparation 5-[(3S)-and N-Tyr-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane (8m)
Operation according to preparation 8a gets 0.079g (74%) title compound (colorless solid) from 0.150g (0.20mmol) 7m.Mp：110.9-112.3℃；[α]
D 25＝-39.65(C?0.7CH
2Cl
2/CH
3OH?1∶1?V/V)；ESI-MS(m/z)：547.3[M+H]
+
Antithrombotic acitivity test in the body of test example 1 The compounds of this invention
1) test materials
Test-compound: the compound that the embodiment of the invention is prepared is numbered 6 respectively, 8a-m;
Positive reference substance is an acetylsalicylic acid
Laboratory animal: the Wistar rat, male, body weight 180-220; Provide by animal portion of the Capital University of Medical Sciences.
Solvent: physiological saline
Polyethylene tube (two kinds of external diameter 1.6mm and 1.3mm), heparin (50IU/ml), Ethylurethanm, silk thread.
2) test method
1. dosage setting
Test-compound 6,8a-m are 10nmol/kg, all adopt the vein single administration.Acetylsalicylic acid is 20mg/Kg.
2. medicine preparation
Test-compound 6,8a-m and acetylsalicylic acid are all used physiological saline solution
3. measuring method
Male SD rat (anaesthetize by body weight 180～220g) abdominal injection Sodital sodium solutions, isolate right common carotid artery and left external jugular vein, put into the long silk thread of 6cm of weighing in advance in the stage casing of polyethylene tube, (50IU/kg) is full of polyethylene tube with heparin-saline, one end is inserted left external jugular vein, with syringe with heparin (3ml/kg), normal saline solution (the 40mg/10ml of acetylsalicylic acid, 3ml/Kg), 6,8a-m (10nmol/kg, normal saline solution 3ml/kg) slowly injects polyethylene tube from the other end, original heparin has been pushed in the left external jugular vein in the pipe at this moment, and major part is a test compound solution in the pipe, then the injectable drug end is inserted right common carotid artery.Blood flows to left external jugular vein from right common carotid artery through polyethylene tube, and middle Herba Clinopodii behind the 15min takes out silk thread and weighs, and gross weight deducts silk thread weight and is wet weight of thrombus
4. statistical method
This experimental data statistics all adopts t check and variance analysis, with
Expression.
5. test-results
The influence that table 1 8a-n forms rat suppository
N=10 a) compares p＜0.01 with physiological saline; B) compare p＜0.05 with physiological saline
As can be seen from Table 1, The compounds of this invention 6,8a-m are compared the difference with significance with physiological saline under 10nmol/kg dosage, are outstanding antithrombotic agent.
Claims (6)
1. have 1 of antithrombotic acitivity, 3-dioxanes compounds, its structural formula are shown in the general formula I:
General formula I
Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
2. a synthetic claim 1 is described 1, and the method for 3-dioxanes compounds may further comprise the steps:
(1) preparation N-[(3S)-and N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) preparation 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol; (3) with 1,2,3, the two pure and mild paranitrobenzaldehyde condensations of 4-tetrahydroisoquinoline acyl Serine generate 5-[1, and 2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (4) with 5-[1,2,3,4 ,-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1,3-dioxane and Fmoc-AA condensation prepared generate 5-[Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-2-p-nitrophenyl-1, the 3-dioxane; (5) 5-(Fmoc-AA-1,2,3,4-tetrahydroisoquinoline-3-formyl radical)-2-p-nitrophenyl-1,3-dioxane alkaline hydrolysis, promptly; Wherein, AA is selected from hydrogen, Val, Leu, Ile, Gly, Ala, Trp, Thr, Met, Asp, Pro, Phe, Lys or Tyr.
3. in accordance with the method for claim 2, it is characterized in that described N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol prepares in accordance with the following methods:
(1) at SOCl
2Existence changes the L-Serine into the L-serine methylester down with methyl alcohol; (2) in the presence of dense HCl and water, change the L-phenylalanine into 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety; (3) at (Boc)
2With 1,2,3,4-Tetrahydroisoquinoli-dicarboxylic acid moiety changed N-tertbutyloxycarbonyl tetrahydroisoquinoline under O and NaOH existed; (4) L-serine methylester and the condensation of N-tertbutyloxycarbonyl tetrahydroisoquinoline generate N-[(3S in the presence of DCC, HOBt)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-the L-serine methylester.
4. in accordance with the method for claim 3, it is characterized in that described 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol prepares in accordance with the following methods:
(1) at NaBH
4Following to N-t-butoxycarbonyl amino acyl-1,2,3 with the THF existence, the reduction of 4-tetrahydroisoquinoline acyl serine methylester generates N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl radical]-L-Serine glycol; (2) in the presence of hydrogenchloride-THF with N-t-butoxycarbonyl amino acyl-1,2,3, the acidolysis of 4-tetrahydroisoquinoline acyl silk glycol generates 1,2,3,4-tetrahydroisoquinoline acyl Serine glycol.
5. pharmaceutical composition is characterized in that: it is described 1 to go up the claim 1 of significant quantity by treatment or prevention, and 3-dioxanes compounds and pharmaceutically acceptable carrier or auxiliary material are formed.
6. claim 1 is described 1, the application of 3-dioxanes compounds in the preparation antithrombotic agent.
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| CN101200493B (en) * | 2006-12-11 | 2011-11-09 | 首都医科大学 | (3S)-N-(L-aminoacyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, preparation method and uses thereof |
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| CN103880770B (en) * | 2014-03-18 | 2017-08-08 | 南通佰华生物医药研究有限公司 | The preparation method of chiral 3 morpholine methanol classes and 3 morpholine formic acid compounds |
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