CN105130893B - A kind of application of the first boc methyl tetrahydro isoquinoline derivative of 1 benzyl 6, preparation method and its platelet aggregation-against - Google Patents
A kind of application of the first boc methyl tetrahydro isoquinoline derivative of 1 benzyl 6, preparation method and its platelet aggregation-against Download PDFInfo
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- CN105130893B CN105130893B CN201510566169.8A CN201510566169A CN105130893B CN 105130893 B CN105130893 B CN 105130893B CN 201510566169 A CN201510566169 A CN 201510566169A CN 105130893 B CN105130893 B CN 105130893B
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- Prior art keywords
- methyl
- boc
- benzyl
- tetrahydro isoquinoline
- platelet aggregation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- QPILYVQSKNWRDD-UHFFFAOYSA-N 1-methyl-1,2,3,4-tetrahydroisoquinoline Chemical class C1=CC=C2C(C)NCCC2=C1 QPILYVQSKNWRDD-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 title claims description 8
- 208000010110 spontaneous platelet aggregation Diseases 0.000 title abstract description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 34
- -1 methyls tetrahydro isoquinoline derivative Chemical class 0.000 claims abstract description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000002252 acyl group Chemical group 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 29
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 7
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- 238000012986 modification Methods 0.000 claims description 6
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
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- 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 claims description 4
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- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940125670 thienopyridine Drugs 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- 238000002627 tracheal intubation Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000003041 virtual screening Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical synthesis field, there is provided a kind of application of 1- benzyls -6- first boc methyls tetrahydro isoquinoline derivative, preparation method and its platelet aggregation-against, and in particular to formula
Description
Technical field
The invention belongs to pharmaceutical synthesis field, is related to a kind of 1- benzyls -6- first boc methyls tetrahydro isoquinoline derivative, prepares
The application of method and its platelet aggregation-against, and in particular to a kind of 1- substituted benzyls-N- alkyl (acyl group) -6- first boc methyl -
The application of 7- methoxyl group -1,2,3,4- tetrahydro isoquinoline derivatives, preparation method and its platelet aggregation-against.
Background technology
Common thrombotic diseases include lower-limb deep veins thrombus, coronary artery thrombosis and cerebral artery thrombosis etc., to people
Life cause serious influence and puzzlement.Antiplatelet drug is the important component of antithrombotic, mainly passes through blocking
Signal path plays a role in the signal transduction or interference cell of the membrane receptor related to thrombosis.ADP is one important
Blood platelet power-assist agent, induce by 2 G- coupling proteins acceptor P2Y1 and P2Y12 acceptors on platelet membrane and accelerate blood
The activation of platelet.P2Y1 and P2Y12 acceptors are to hematoblastic activation and polymerize particularly significant.In addition research has shown that P2Y12
Acceptor gathers to ADP induced platelets to play an important roll, and is a more efficiently therapy target of antiplatelet drug.
Clopidogrel is second generation Thienopyridines P2Y12 receptor antagonists, but effect is not strong, work slow and individual
Difference is obvious.(reaction equation is metabolized inside the research clopidogrel such as Trenk D, Kristensen S D, Hochholzer W
1) clopidogrel for, finding to be absorbed by the body has the part more than 85% to be hydrolyzed into inactive carboxylic by the carboxy-lesterase in blood plasma
Acid metabolic thing SR26334, the only medicine of fraction are by liver cell pigment enzyme P450 system oxidations into 2- oxo clopidogrels.
In the liver cell pigment enzyme P450 system oxidations of second step, the 2- oxo clopidogrels only close to 50% are metabolised to open loop
Thiol active metabolin, and other 50% 2- oxos clopidogrels are equally hydrolyzed into inactive carboxylic acid by carboxy-lesterase and are metabolized
Thing.Last active metabolite is irreversibly combined with blood platelet P2Y12 acceptors by two sulphur covalent bonds to be made to play antiplatelet
With.And prasugrel replaces the methoxycarbonyl group in clopidogrel with cyclopropyl carbonyl, while thiphene ring is modified, so both
Avoid carboxy-lesterase and be hydrolyzed into inactive metabolin, reduce metabolic step (reaction equation 2) of the medicine in liver again,
Clopidogrel effect not it is strong, work the slow and obvious basic reason of individual difference also it is apparent.Thus, it is possible to draw
One guess：Ester group in clopidogrel structure may be not essential groups, and the group size being connected with ketone group
It is relevant, meanwhile, the carboxylic acid in active metabolite may be essential groups.
The metabolic process of clopidogrel
The metabolic process of prasugrel
Neferine is a kind of bisbenzylisoquinoline alkaloid extracted in lotus nut.It is external that research finds that it has
The platelet aggregation of anti-ADP inductions, and adhesion and blood platelet blood of the blood platelet to collagen in Mice Body can be significantly reduced
The formation of bolt；In pulmonary embolism model test, neferine can prevent mouse from dying from acute lung thrombus.
6,7- dimethoxys-the N- of East China University of Science Gao Lindong synthesis, which is acylated benzyl tetrahydro isoquinoline class compound, to be had
Platelet aggregation inhibitory activity, wherein compound IfActivity is IC50=165 μm of ol/L.Also related in Japan Patent JP63174932A
And the platelet aggregation inhibitory activity of 1- benzyl -1,2,3,4- tetrahydroisoquinolines.More 1- benzyl tetrahydro isoquinolines are studied at present
In structure, the bit substituent of isoquinolin 6,7 is mostly H, MeO, PhCH2O or 6,7-OCH2O, rare 6 first boc methyl substitutions of research.
The present invention studies the problem of existing for targeting P2Y12 acceptors antiplatelet drug, uses for reference existing medicine chlorine pyrrole lattice
The metabolite of thunder, with the virtual screening means of Computer-Aided Drug Design, to clearly having the blood of anti-ADP inductions
The natural activity monomer neferine of platelet aggregation carries out structure of modification, a kind of new 1- benzyl -6- methoxy carbonyl first of design
Base tetrahydroisoquinolicompounds compounds.
The content of the invention
The present invention uses for reference the metabolin of P2Y12 receptor antagonist clopidogrels, to have anti-ADP induction blood in medicinal plant
The neferine of platelet aggregation activity is lead compound, using P2Y12 acceptors as target, is set by area of computer aided medicine
Meter, has designed and synthesized a kind of new 1- benzyl -6- first boc methyl tetrahydroisoquinolicompounds compounds.The purpose of the present invention is
There is provided the novel tetrahydro isoquinoline compound with good platelet aggregation inhibitory activity, and in particular to a kind of 1- substitutes benzyl
Base -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydroisoquinolicompounds compounds and the like.
Technical scheme：1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives, it is that a kind of 1- substitutes benzyl
Base-N- alkyl (acyl group) -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydro isoquinoline derivatives, the derivative is structure
Compound of the formula as shown in formula I：
Wherein：R1For hydrogen, halogen, alkyl, phenyl, substituted-phenyl, heteroaromatic, substitution heteroaromatic, R3-X-；
R2For C1-C10Alkyl, benzyl, substituted benzyl, C1-C10Alkyl acyl, C6-C12Aryl-acyl, amino acid, amino acid
Salt or C6-C12Aryl substitutes amine formyl；
R3For alkyl, phenyl, substituted-phenyl, heteroaromatic, substitution heteroaromatic；
X is-O- ,-NR4- ,-S- or optionally substitute C1-C4- alkylidene；
R4For hydrogen or C1-C6- alkyl.
Described 1- benzyl -6- first boc methyls tetrahydro isoquinoline derivative is the compound of formula II：
R5=H, halogen, alkyl, alkoxy, phenyl, substituted-phenyl, heteroaromatic, substitution heteroaromatic.
Described 1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives are：
(1) 1- [(1,1 '-xenyl) -4- methyl] -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydroisoquinolines,
Structural formula is
(2) 1- [(1,1 '-xenyl) -4- methyl]-N- acetyl group -6- first boc methyl -7- methoxyl groups -1,2,3,4- four
Hydrogen isoquinoline, structural formula are
(3) 1- [(1,1 '-xenyl) -4- methyl]-N- [(4 '-nitro) phenylacetyl group] -6- first boc methyl -7- methoxies
Base -1,2,3,4- tetrahydroisoquinolines, structural formula are
(4) 1- [(1,1 '-xenyl) -4- methyl]-N- (Boc- glycine aminoacyl) -6- first boc methyl -7- methoxies
Base -1,2,3,4- tetrahydroisoquinolines, structural formula are
(5) 1- [(1,1 '-xenyl) -4- methyl]-N- benzyls -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydrochysenes
Isoquinolin, structural formula are
(6) 1- [(1,1 '-xenyl) -4- methyl]-N- (glycine aminoacyl) -6- first boc methyl -7- methoxyl group -1,
2,3,4- tetrahydroisoquinolines, structural formula are
It is a further object of the present invention to provide the preparation method of 1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives,
Reaction scheme is as follows：
The preparation process of 1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives shown in above-mentioned formula I is as follows：
(1) in molar ratio 1:0~1.2 will contain R1The phenylacetic acid of substituent reacts with being added to methoxyphenethylamine hydrochloride
In device, acetonitrile as solvents, in the presence of HBTU and triethylamine, 15~60min of normal-temperature reaction, the amide derivatives substituted；
(2) using benzenethiol as raw material, toluene is solvent, adds 1~1.4eq, 110 DEG C of back flow reactions of metallic sodium, then be added dropwise 1
~1.5eq methyl chloroacetates react 1~2h generation 2- benzene methyl thioglycolates；Then 1.1 are added dropwise under the conditions of -10 DEG C of ice salt bath
~1.3eq sulfonic acid chlorides react 1~2h generation chloro- 2- benzene methyl thioglycolates of alkylating reagent 2-；The acid amides that step (1) is obtained
Derivative is dissolved in anhydrous methylene chloride, nitrogen charging gas shielded, and 1mmol is pressed under stirring at normal temperature:Nothing is slowly added dropwise in 0.2mL ratio
Water butter of tin solution, is added dropwise, stir add after 10~20min 1~1.25eq alkylating reagents normal-temperature reaction 10~
20min obtains the methyl substituted amide derivatives of benzene sulfydryl methoxy carbonyl；
(3) amide derivatives that step (2) obtains are dissolved in ethanol, by 1mmol:0.5~1.5g ratio adds thunder
Buddhist nun's nickel, under nitrogen protection, stirring at normal temperature reacts 2~4h, obtains the methyl substituted amide derivatives of methoxy carbonyl；
(4) amide derivatives for obtaining step (3) are by 1mmol:5mL ratio is dissolved in POCl3,95~115 DEG C
2~5h of back flow reaction, vacuum rotary steam removes POCl3, by 1mmol:5mL ratio adds dichloromethane, adds and goes under ice bath
Ionized water, after adjusting pH value to alkalescence, dichloromethane extraction, organic phase anhydrous sodium sulfate drying filters, and vacuum rotary steam must be consolidated
Body；Ring-closure reaction crude product is dissolved in dichloromethane, by 1mmol:5mL ratio addition methanol, the lower addition 1 of ice bath stirring~
2eq sodium borohydrides, 1~2h of reaction obtain 1- substituted benzyl -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydroisoquinolines；
(5) to the amino of 1- substituted benzyl -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydro isoquinoline derivatives
It is alkylated and is acylated respectively modification.
Described 1- benzyl -6- first boc methyls tetrahydro isoquinoline derivative is used to prepare treatment thrombus medicine.
1- benzyls -6- first boc methyl tetrahydro isoquinoline derivatives provided by the invention, through Instrumental Analysis, the correct nothing of structure
By mistake.The preparation method of the 1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives of the present invention is simple and easy, and cost is relatively low.Should
Analog derivative, which carries out external platelet aggregation inhibitory activity test display, has certain platelet aggregation inhibitory activity.Preparing anti-blood
Bolt drug field has good practical value and application prospect.
Embodiment
Below in conjunction with technical scheme, embodiment of the invention is further illustrated.
If the method employed in the embodiment of the present invention does not provide specific operating condition or operating procedure, its phase
It is known to ordinary skill in the art to answer technology, or is carried out according to the condition proposed by material supplier and method.
The system of the 2- of embodiment 1 [(1,1 '-xenyl) -4- bases]-N- (4- methoxyphenethyls) acetamides (compound 9)
It is standby
1mmol is weighed to methoxyphenethylamine hydrochloride, 1.0~1.2mmol felbinacs, in 25mL single necked round bottom flask
In, 5mL acetonitriles dissolving raw material, 4.2mmol triethylamines are added, water-bath magnetic agitation at 25 DEG C.Peptide coupling agent is added after 5min
HBTU 0.4930g (1.3mmol), 15~60min reaction are complete.Vacuum rotary steam removes acetonitrile, obtains yellow solid, 50mL bis-
Chloromethanes is dissolved, deionized water washing (50mL × 3), 50mL saturated common salt water washings, and dichloromethane layer is done with anhydrous sodium sulfate
It is dry, filter, vacuum rotary steam removes solvent and obtains white solid.Column chromatography chromatogram separates (dichloromethane：Petroleum ether：Ethyl acetate=
100:25:4) white solid powder 0.3351g, yield 97% are obtained.1H NMR(CDCl3,400MHz)δ:7.59 (d, J=
7.6Hz, 2H, H-2 ", 6 "), 7.54 (d, J=8.0Hz, 2H, H-4,8), 7.45 (dd, J1=7.2Hz, J2=7.6Hz, 2H, H-
3 ", 5 "), 7.36 (t, J=7.2Hz, 1H, H-4 "), 7.24 (d, J=8.0Hz, 2H, H-5,7), 6.94 (d, J=8.4Hz, 2H,
H-4', 8'), 6.74 (d, J=8.4Hz, 2H, H-5', 7'), 5.39 (brs, 1H, NH), 3.69 (s, 3H, OCH3),3.60(s,
2H, H-2), 3.45 (q, J=6.8Hz, 2H, H-1'), 2.67 (t, J=6.8Hz, 2H, H-2')；13C NMR(CDCl3,
100MHz)δ:170.9(C-1),158.2(C-6'),140.5(C-1”),140.2(C-6),133.9(C-3),130.6(C-
3'),129.9(C-4',8'),129.6(C-4,8),128.9(C-3”,5”),127.6(C-5,7),127.5(C-3'),127.0
(C-2”,6”),114.0(C-5',7'),55.1(OCH3),43.4(C-2),40.9(C-1'),34.6(C-2'),ESI-MS m/
z:346.42[M+H]+。
The 2- of embodiment 2 [(1,1 '-xenyl) -4- bases]-N- (3- benzene sulfydryl first boc methyl -4- methoxyphenethyls)
The preparation of acetamide (compound 10)
(1) preparation of 2- benzene methyl thioglycolate (compound 7).2054 μ L (20.0mmol) benzenethiols are measured in 100mL
In three-necked flask, 30mL toluene is added, 0.5060g (22.0mmol) metallic sodium is cut into small pieces and added in bottle, is flowed back at 110 DEG C
Reaction, TLC monitoring reaction process.After reaction completely, 20.0~30.0mmol methyl chloroacetates are added dropwise with constant pressure funnel,
TLC monitorings are reacted, and react complete after 1~2h.70mL ethyl acetate is added, 100mL deionized waters are washed 3 times, organic phase nothing
Aqueous sodium persulfate is dried, and is filtered, and vacuum rotary steam obtains pale yellow oily liquid 1 after removing solvent.Column chromatography chromatogram separates (acetic acid second
Ester：Petroleum ether=1:40) 3.3167g weak yellow liquids, yield 91% are obtained.
(2) preparation of the chloro- 2- benzene methyl thioglycolates (compound 8) of 2-.311 μ L are added into 50mL three-necked flasks
(2.0mmol) compound 7, the dissolving of 2mL dichloromethane, magnetic agitation.2.2~2.6mmol sulphonyl is added dropwise at -10 DEG C of ice salt bath
Chloro- 2mL dichloromethane mixed liquor.TLC monitorings are reacted, and react complete after 1h.Reaction solution is poured into frozen water, saturated sodium bicarbonate
The aqueous solution neutralizes, and dichloromethane extraction (20mL × 2), organic phase anhydrous sodium sulfate drying, filters, and vacuum rotary steam removes solvent
Pale yellow oily liquid is obtained afterwards.Column chromatography chromatogram separates (dichloromethane：Petroleum ether=1:10) 0.3339g pale yellow oily liquids are obtained
Body, yield 77%.
(3) weigh 0.6909g (2.0mmol) compound 9 and in 50mL three-necked flasks, load onto two 10mL constant pressure addition
Funnel, a funnel add 2.0~2.5mmol compounds 8, N2After displacement 3 times, into reaction bulb, injection 10mL steams dichloromethane again
Alkane dissolved compound 9,2mL steam dchloromethane compound 8 again；It is another that the injection of 0.4mL anhydrous stannic chlorides is drawn with needle tubing
Constant pressure funnel, 4mL steam dchloromethane, stirred at 23 DEG C of water-bath again.Anhydrous stannic chloride is slowly dropped into reaction bulb
In, the compound 8 of dilution is added after 15min.Reacted after 10~20min complete.Reactant is slowly added in 30mL frozen water, two
Chloromethanes extracts (30mL × 2), and organic phase is washed till neutrality with 60mL saturated sodium bicarbonates, and 60mL saturated common salt water washings are anhydrous
Sodium sulphate is dried, and is filtered, and vacuum rotary steam removes solvent, obtains colorless oil.Column chromatography chromatogram separates (dichloromethane：Petroleum ether：
Ethyl acetate=100:25:8) colorless viscous thing 0.7043g, yield 67% are obtained.1H NMR(CDCl3,400MHz)δ:7.58
(d, J=7.2Hz, 2H, H-2 ", 6 "), 7.55 (d, J=8.0Hz, 2H, H-4,8), 7.44 (dd, J1=7.2Hz, J2=8.0Hz,
2H, H-3 ", 5 "), 7.33~7.37 (m, 3H, H-5,7,4 "), 7.23~7.26 (m, 5H, PhS), 7.21 (d, J=2.0Hz,
1H,H-4'), 6.91(dd,J1=2.0Hz, J2=8.4Hz, 1H, H-8'), 6.67 (d, J=8.4Hz, H-7'), 5.40 (brs,
1H,NH),5.36(s,1H,H-9'),3.68(s,3H,H-12')；13C NMR(CDCl3,100MHz)δ:171.3(C-10'),
170.9(C-1),155.1(C-6'),140.6(C-1”),140.0(C-6),134.2(PhS-C-1),134.1(C-3),134.6
(PhS-C-2,6)131.0(C-4'),129.9(C-3”,5”),129.7(C-3'),129.6(C-4”),128.9(C-4,8),
128.8(PhS-C-3,5),127.8(C-8'),127.5(C-2”,6”),127.4(PhS-C-4),127.0(C-5,7),124.3
(C-5'),111.0(C-7'),55.7(C-12'),52.6(C-11'),48.9(C-9'),43.4(C-2),40.8(C-1'),
34.7(C-2'),ESI-MS m/z:548.38[M+Na]+。
The 2- of embodiment 3 [(1,1 '-xenyl) -4- bases]-N- (3- first boc methyl -4- methoxyphenethyls) acetamide
The preparation of (compound 11)
3.9813g (7.6mmol) compound 10 is weighed into 250mL single-necked flasks, the dissolving of 80mL ethanol.Raney's nickel second
Alcohol washing water removal, adds 11.4g Raney's nickels, and hydrogen is replaced 3 times, and 25 DEG C of magnetic force of water-bath are stirred vigorously under hydrogen, and 2~4h has reacted
Entirely.Reaction solution suction filtered through kieselguhr, dichloromethane washing filter cake, filtrate decompression is rotated into removing solvent and obtains white solid
3.0500g yield 97%.1H NMR(CDCl3,400MHz)δ:7.59 (d, J=7.2Hz, 2H, H-2 ", 6 "), 7.55 (d, J=
8.0Hz,2H,H-4,8),7.44(dd,J1=7.2Hz, J2=7.2Hz, 2H, H-3 ", 5 "), 7.35 (t, 1H, J=7.2Hz, 1H,
H-4 "), 7.26 (d, J=8.0Hz, 2H, H-5,7), 6.90 (d, J=1.4Hz, H-4'), 6.89 (dd, 1H, J1=1.4Hz, J2
=8.0Hz, H-8'), 6.68 (d, J=8.0Hz, H-7'), 5.45 (brs, 1H, NH), 3.70 (s, 3H, H-12'), 3.67 (s,
3H, H-11'), 3.57 (s, 2H, H-2), 3.47 (s, 2H, H-9'), 3.45 (q, J=6.8Hz, 2H, H-1'), 2.68 (t, J=
6.8Hz, 2H, H-2'), 3.65 (s, 3H, H-11'), 3.58 (s, 2H, H-2), 3.39 (q, J=6.8Hz, 2H, H-1'), 2.66
(t, J=6.8Hz, 2H, H-2')；13C NMR(CDCl3,100MHz)δ:172.2(C-10'),170.8(C-1),156.2(C-
6'),140.5(C-1”),140.2(C-6),134.0(C-3),131.8(C-4'),130.5(C-3'),129.9(C-3”,5”),
128.9(C-4,8),128.6(C-4”),127.4(C-8'),127.6(C-2”,6”),127.0(C-5,7),123.1(C-5'),
110.6(C-7'),55.5(C-12'),51.9(C-11'), 43.5(C-2),40.8(C-1'),34.6(C-9'),34.6(C-
2')；ESI-MS m/z:418.34[M+H]+。
The 1- of embodiment 4 [(1,1 '-xenyl) -4- methyl] -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydrochysenes are different
The preparation of quinoline (compound 1)
3.2487g (7.7mmol) compound 11 is weighed in 250mL single-necked flasks, addition 40mL POCl3s, 95~
115 back flow reactions.Reacted after 2~5 hours complete.Vacuum rotary steam removes POCl3, dichloromethane 150mL is added, under ice bath
It is slowly added to deionized water 100mL, 2mol/L sodium hydrate aqueous solution and adjusts pH value to alkalescence, dichloromethane extraction (150mL ×
2), organic phase anhydrous sodium sulfate drying, filter, vacuum rotary steam removes solvent and obtains 4.1830g red solids.Ring-closure reaction is thick
Product is dissolved in 25mL dichloromethane, addition 25mL methanol, magnetic agitation under ice bath, is slowly added to 0.3448g (9.1mmol) boron
Sodium hydride, reaction in 1~2 hour are complete.Reaction solution pH is adjusted to faintly acid with 2mol/L hydrochloric acid solutions, vacuum rotary steam removes organic
200mL dichloromethane lysates are added after solvent, the washing of 200mL saturated sodium bicarbonate aqueous solutions, make pH to alkalescent, dichloro
Methane extracts (200mL × 2), merges organic layer and is obtained yellow with anhydrous sodium sulfate drying, suction filtration, vacuum rotary steam removing solvent and consolidated
Body；Column chromatography chromatogram separates (petroleum ether：Ethyl acetate：Triethylamine=8:1:1%) faint yellow solid 1.9996g, yield are obtained
64%.1H NMR(CDCl3,400MHz)δ:7.59(dd,J1=1.2Hz, J2=8.4Hz, 2H, H-2 ", 6 "), 7.57 (d, J=
8.0Hz,2H,H-4',6'),7.43(dd,J1=7.2Hz, J2=8.4Hz, 2H, H-3 ", 5 "), 7.34 (d, 2H, J=8.0Hz,
H-3',7'),7.33(td,J1=1.2Hz, J2=7.2Hz, 1H, H-4 "), 7.24 (s, 1H, H-6), 6.90 (s, 1H, H-9),
4.23(dd,J1=4.4Hz, J2=9.2Hz, 1H, H-1), 3.75 (s, 3H, H-11'), 3.69 (s, 3H, H-10'), 3.60 (d, J
=2.4Hz, 2H, H-8'), 3.26 (dd, J1=4.43Hz, J2=13.6Hz, 1H, H-1'b), 3.21 (dd, J1=5.6Hz, J2
=12.0Hz, 1H, H-3a), 3.00 (dd, J1=9.2Hz, J2=13.6Hz, 1H, H-1'a), 2.93 (m, 1H, H-3b), 2.94
(m,2H,H-4)；13C NMR(CDCl3,100MHz)δ:172.0(C-9'),155.6(C-8),140.5(C-1”),140.1(C-
5'),135.2(C-2'),131.3(C-10),130.3(C-6),130.6(C-3',7'),128.9(C-3”,5”),127.4(C-
4”),127.4(C-4',6'), 126.9(C-2”,6”),123.1(C-5),123.0(C-7),109.1(C-9),55.3(C-
1),55.1(C-11'),52.0(C-10'),40.5(C-3),39.0(C-1'),35.2(C-8'),24.7(C-4)；ESI-MS
m/z:402.27[M+H]+。
The 1- of embodiment 5 [(1,1 '-xenyl) -4- methyl]-N- acetyl group -6- first boc methyl -7- methoxyl group -1,2,
The preparation of 3,4- tetrahydroisoquinolines (compound 2)
58.4mg (0.14mmol) compound 11 is weighed in 25mL single necked round bottom flask, adds the dissolving of 1mL ethyl acetate
Raw material, 1mL saturated sodium bicarbonate aqueous solutions are added, magnetic agitation under 2.5 DEG C of ice-water baths, 20 μ L are added dropwise into reaction solution
(0.28mmol) chloroacetic chloride (is dissolved in 20 μ L ethyl acetate), TLC monitoring reactions, reacts complete after 30min.30mL water is added,
30mL ethyl acetate extracts, and with being filtered after anhydrous sodium sulfate drying 1h, vacuum rotary steam removes solvent and obtains colorless oil organic phase,
Column chromatography chromatogram separates (petroleum ether：Ethyl acetate=1:1) white solid 58.0mg, yield 93% are obtained.(T)-2:1H NMR
(CDCl3,400MHz)δ:7.58 (m, 2H, H-2 ", 6 "), 7.44 (d, J=7.6Hz, 2H, H-4', 6'), 7.43 (m, 2H, H-
3 ", 5 "), 7.33 (t, J=8.0Hz, 1H, H-4 "), 7.18 (d, 2H, J=7.6Hz, H-3', 7'), 6.93 (s, 1H, H-6),
6.15(s,1H,H-9),5.74(dd,J1=5.6, J2=8.4Hz, 1H, H-1), 3.69 (s, 3H, H-12'), 3.66 (m, 1H, H-
3b), 3.58 (s, 2H, H-10'), 3.54 (m, 1H, H-3a), 3.49 (s, 3H, H-13'), 3.22 (dd, J1=5.6, J2=
12.8Hz,1H,H-1'b),3.02(dd,J1=8.4, J2=12.8Hz, 1H, H-1'a), 2.82 (m, 1H, H-4b), 2.74 (m,
1H,H-4a),2.15(s,3H,H-9')；13C NMR(CDCl3,100MHz)δ:172.3(C-11'),169.4(C-8'),155.5
(C-8),140.9(C-1”),139.3(C-5'),137.3(C-2'),136.4(C-10),130.5(C-6),130.3(C-3',
7'),128.7(C-3”,5”),127.4(C-4”),127.0(C-2”,6”),126.8(C-4',6'),125.3(C-5),121.6
(C-7),109.0(C-9),55.3(C-13'),54.4(C-1),51.9(C-12'),42.0(C-1'),41.9(C-3),35.3
(C-10'),28.1(C-4),22.1(C-9')；(C)-2:1H NMR(CDCl3,400MHz)δ:7.56(m,4H,H-2”,6”,4',
6'), 7.45 (m, 2H, H-3 ", 5 "), 7.35 (t, J=8.0Hz, 1H, H-4 "), 7.26 (d, 2H, J=6.8Hz, H-3', 7'),
6.98(s,1H,H-6),6.52(s,1H,H-9),4.89(dd,J1=4.8, J2=9.2Hz, 1H, H-1), 4.79 (dd, J1=
5.2Hz,J2=13.2Hz, 1H, H-3b), 4.75 (s, 3H, H-13'), 3.71 (s, 3H, H-12'), 3.61 (s, 2H, H-10'),
3.20(m,2H,H-3a,1'a),3.12(dd,J1=4.8, J2=13.6Hz, 1H, H-1'b), 2.89 (m, 1H, H-4b), 2.70
(m,1H,H-4a),1.62(s,3H,H-9')；13C NMR(CDCl3,100MHz)δ:172.2(C-11'),169.6(C-8'),
155.7(C-8),140.6(C-1”),140.0(C-5'),136.8(C-2'),136.1(C-10),131.6(C-6),130.0
(C-3',7'),128.8(C-3”,5”),127.4(C-4”),127.1(C-4',6'),126.9(C-2”,6”),126.4(C-
5),122.4(C-7),109.9(C-9),59.7(C-1),55.6(C-13'),52.0(C-12'),42.7(C-1'),35.4(C-
10'),35.3(C-3),27.4(C-4),21.1(C-9')；ESI-MS m/z:444.32[M+H]+。
The 1- of embodiment 6 [(1,1 '-xenyl) -4- methyl]-N- [(4 '-nitro) phenylacetyl group] -6- first boc methyl -
The preparation of 7- methoxyl group -1,2,3,4- tetrahydroisoquinolines (compound 3)
48.0mg (0.12mmol) compound 11 is weighed in 25mL single necked round bottom flask, it is former to add the dissolving of 1.5mL acetonitriles
Material, the paranitrophenylacetic acid 21mg (0.12mmol) weighed up is added, add the μ L (0.43mmol) of triethylamine 60, magnetic under 25 DEG C of water-baths
Power is stirred, and 57.2mg (0.15mmol) HBTU, TLC monitoring reactions are added after 5min；A plate is extracted reaction solution after 30min, has been reacted
Full cut-off only reacts.Vacuum rotary steam removes acetonitrile, the dissolving of 20mL dichloromethane, deionized water washing (20mL × 3), 20mL saturations food
Salt water washing, organic phase anhydrous sodium sulfate drying, filter, vacuum rotary steam removes solvent and obtains yellow oil.Column chromatography color
Spectrum separation (petroleum ether：Ethyl acetate=3：1) pale yellowish oil 64.3mg, yield 99% are obtained.(T)-3:1H NMR(CDCl3,
400MHz)δ:8.08 (d, J=8.4Hz, 2H, H-12', 14'), 7.59 (m, 2H, H-2 ", 6 "), 7.49 (d, J=7.6Hz, 2H,
H-4', 6'), 7.43 (m, 2H, H-3 ", 5 "), 7.38 (m, 1H, H-4 "), 7.24 (d, 2H, J=8.4Hz, H-11', 15'),
7.20 (d, 2H, J=7.6Hz, H-3', 7'), 6.93 (s, 1H, H-6), 6.24 (s, 1H, H-9), 5.67 (dd, J1=6.8Hz, J2
=8.0Hz, 1H, H-1), 3.84 (d, J=15.2Hz, 1H, H-9'a), 3.96 (d, J=15.2Hz, 1H, H-9'b), 3.74 (m,
1H, H-3a), 3.71 (s, 3H, H-18'), 3.57 (d, J=4.4Hz, 2H, H-16'), 3.52 (m, 1H, H-3b), 3.51 (s,
3H,H-19'),3.22(dd,1H, J1=6.8Hz, J2=13.2Hz, H-1'a), 3.22 (dd, 1H, J1=8.0Hz, J2=
13.2Hz,H-1'b),2.75(m,2H,H-4)；13C NMR(CDCl3,100MHz)δ:172.2(C-17'),168.3(C-8'),
155.7(C-8),146.9(C-13'),142.7(C-10'),140.7(C-1”),139.4(C-5'),136.9(C-2'),
136.2(C-10),130.8(C-6),130.3(C-3',7'),130.0(C-11',15',13'),128.9(C-3”,5”),
127.3(C-4”),126.9(C-4',6'),126.8(C-2”,6”),124.8(C-5),123.8(C-12',14'),122.0
(C-7),109.7(C-9),55.4(C-19'),54.6(C-1),52.0(C-18'),42.0(C-1'),41.3(C-3),40.7
(C-9'),35.2(C-16'),28.1(C-4)；(C)-3:1H NMR(CDCl3,400MHz)δ:7.93 (d, J=8.4Hz, 2H, H-
12', 14'), 7.63 (d, J=7.2Hz, 2H, H-4', 6'), 7.60 (d, J=7.6Hz, 2H, H-2 ", 6 "), 7.46 (m, 2H, H-
3 ", 5 "), 7.35 (d, 2H, J=7.2Hz, H-3', 7'), 7.34 (m, 1H, H-4 "), 7.00 (s, 1H, H-6), 6.86 (d, 2H, J
=8.4Hz, H-11', 15'), 6.64 (s, 1H, H-9), 5.00 (dd, J1=4.4Hz, J2=9.2Hz, 1H, H-1), 4.84 (dd,
J1=5.6Hz, J2=12.8Hz, 1H, H-3a), 3.82 (s, 3H, H-19'), 3.68 (s, 3H, H-18'), 3.62 (s, 2H, H-
16'), 3.32 (d, J=16.4Hz, 1H, H-9'a), 3.31 (m, 1H, H-3b), 3.23 (m, 2H, H-1'), 2.93 (m, 1H, H-
4a), 3.96 (d, J=16.4Hz, 1H, H-9'b), 2.75 (m, 1H, H-4b)；13C NMR(CDCl3,100MHz)δ:172.2(C-
17'),168.5(C-8'),156.0(C-8),146.7(C-13'),142.8(C-10'),140.4(C-1”),140.3(C-
5'),136.9(C-2'),135.8(C-10),131.8(C-6),130.5(C-13'),130.3(C-11',15'),129.9(C-
3',7'),129.0(C-3”,5”),127.7(C-4”),127.6(C-4',6'),126.8(C-2”,6”),126.1(C-5),
123.3(C-12',14'),122.8(C-7),108.9(C-9),59.1(C-1),55.7(C-19'),52.0(C-18'),42.4
(C-1'),39.4(C-9'),35.6(C-3),35.4(C-16'),27.4(C-4)；ESI-MS m/z:565.37[M+H]+。
The 1- of embodiment 7 [(1,1 '-xenyl) -4- methyl]-N- (Boc- glycine aminoacyl) -6- first boc methyls -7-
The preparation of methoxyl group -1,2,3,4- tetrahydroisoquinolines (compound 4)
Method is the same as embodiment 5, product column chromatography chromatogram separation (petroleum ether：Ethyl acetate=3:1) white powder is obtained, is received
Rate 97%.(T)-4:1H NMR(CDCl3,400MHz)δ:7.56 (m, 2H, H-2 ", 6 "), 7.49 (d, J=8.4Hz, 2H, H-4',
6'), 7.43 (m, 2H, H-3 ", 5 "), 7.32 (t, J=8.0Hz, 1H, H-4 "), 7.15 (d, 2H, J=8.4Hz, H-3', 7'),
6.93(s,1H,H-6),6.18(s,1H,H-9),5.67(dd,J1=5.6Hz, J2=8.4Hz, 1H, H-1), 5.55 (s, 1H,
), NH 4.05 (d, J=16.8Hz, 1H, H-9'a), 3.96 (d, J=16.8Hz, 1H, H-9'b), 3.69 (s, 3H, H-17'),
3.58 (m, 1H, H-3a), 3.57 (s, 2H, H-15'), 3.52 (m, 1H, H-3b), 3.51 (s, 3H, H-18'), 3.22 (dd, 1H,
J1=5.6Hz, J2=13.2Hz, H-1'a), 3.22 (dd, 1H, J1=8.4Hz, J2=13.2Hz, H-1'b), 2.83 (m, 1H,
H-4a),2.75(m,1H,H-4b),1.45(s,9H,H-12',13',14')；13C NMR(DMSO-d6,100MHz)δ:172.0
(C-16'),168.2(C-8'),156.1(C-10'),155.6(C-8),140.4(C-1”),138.4(C-5'),138.1(C-
2'),137.0(C-10),131.4(C-6),130.5(C-3',7'),129.4(C-3”,5”),127.7(C-4”),127.1(C-
2”,6”),126.9(C-4',6'),125.8(C-5),121.9(C-7),110.1(C-9),78.3(C-11'),55.8(C-
18'),54.2(C-1),52.0(C-17'),42.3(C-9'),41.1(C-3),39.0(C-1'),35.3(C-15'),28.6
(C-12'~14'), 27.8 (C-4)；(C)-4:1H NMR(CDCl3,400MHz)δ:7.58(m,2H,H-2”,6”),7.55(d,J
=8.0Hz, 2H, H-4', 6'), 7.42 (m, 2H, H-3 ", 5 "), 7.35 (m, 1H, H-4 "), 7.24 (d, 2H, J=8.0Hz, H-
3',7'),6.96(s,1H,H-6),6.40(s,1H,H-9),5.29(s,1H,NH),4.81(dd,J1=5.6Hz, J2=
8.4Hz,1H,H-1),4.70(ddd,J1=2.0Hz, J2=6.0Hz, J3=12.8Hz, 1H, H-3a), 3.96 (d, J=
16.4Hz, 1H, H-9'a), 3.70 (s, 3H, H-18'), 3.70 (s, 3H, H-17'), 3.60 (s, 2H, H-15'), 3.52 (ddd,
J1=1.2Hz, J2=4.8Hz, J3=12.8Hz, 1H, H-3b), 3.17 (dd, 1H, J1=8.4Hz, J2=13.6Hz, H-1'a),
3.13(dd,1H,J1=5.6Hz, J2=13.6Hz, H-1'b), 3.13 (d, J=16.8Hz, 1H, H-9'b), 2.92 (m, 1H, H-
4a),2.70(m,1H,H-4b),1.36(s,9H,H-12',13',14')；13C NMR(DMSO-d6,100MHz)δ:172.0(C-
16'),168.1(C-8'),155.8(C-10'),155.7(C-8),140.5(C-1”),139.0(C-5'),138.8(C-2'),
136.9(C-10),131.7(C-6),130.6(C-3',7'),129.3(C-3”,5”),127.7(C-4”), 127.1(C-2”,
6”),126.7(C-4',6'),125.8(C-5),122.2(C-7),110.2(C-9),78.2(C-11'),57.1(C-1),
56.0(C-18'),52.0(C-17'),41.8(C-9'),41.7(C-3),35.0(C-1'),35.3(C-15'),28.5(C-
12'~14'), 27.1 (C-4)；ESI-MSm/z:559.08[M+H]+。
The 1- of embodiment 8 [(1,1 '-xenyl) -4- methyl]-N- benzyl -6- first boc methyl -7- methoxyl group -1,2,3,
The preparation of 4- tetrahydroisoquinolines (compound 5)
Weigh 51.8mg (0.13mmol) compound 11 to be placed in 25mL single-necked flasks, add 1.3mL DMF dissolving raw materials,
Add 22 μ L (0.19mmol) bromobenzyls, 73.18mg (0.23mmol) cesium carbonate, stirring reaction under 25 DEG C of water-baths.TLC monitorings are anti-
Should, 30min reactions are complete.30mL dichloromethane is added, is washed (30mL × 3), organic layer anhydrous sodium sulfate drying, is filtered,
Vacuum rotary steam removes solvent and obtains yellow oil.Column chromatography chromatogram separates (petroleum ether：Ethyl acetate=6:1) yellow oily production is obtained
Thing 45.0mg, yield 73%.1H NMR(CDCl3,400MHz)δ:7.60(dd,J1=1.2Hz, J2=8.4Hz, 2H, H-2 ",
6 "), 7.49 (d, J=8.0Hz, 2H, H-4', 6'), 7.44 (dd, J1=7.2Hz, J2=8.4Hz, 2H, H-3 ", 5 "), 7.34
(td,J1=1.2Hz, J2=7.2Hz, 1H, H-4 "), 7.20 (m, 3H, H-10', 11', 12'), 7.16 (d, 2H, J=8.0Hz,
H-3', 7'), 7.15 (d, 2H, J=8.0Hz, H-9', 14'), 6.93 (s, 1H, H-6), 6.16 (s, 1H, H-9), 3.84 (t, J
=7.6Hz, 1H, H-1), 3.81 (d, J=13.6Hz, 1H, H-8'a), 3.74 (d, J=13.6Hz, 1H, H-8'b), 3.70 (s,
3H, H-18'), 3.58 (d, J=2.4Hz, 2H, H-8'), 3.54 (s, 3H, H-17'), 3.37 (m, 2H, H-1'a), 3.20 (dd,
J1=7.6Hz, J2=13.6Hz, 1H, H-1'a), 2.92 (m, 3H, H-3,4b), 2.51 (m, 1H, H-4a)；13C NMR(CDCl3,
100MHz)δ:172.6(C-16'),155.1(C-8),141.2(C-1”),139.4(C-5',9'),138.9(C-2'),137.9
(C-10),131.3(C-6),130.3(C-3',7'),128.8(C-3”,5”),128.7(C-12'),128.1(C-10',11',
13',14'),127.1(C-4”),127.0(C-4',6'),126.8(C-2”,6”),125.9(C-5),121.2(C-7),
110.3(C-9),62.6(C-1),57.7(C-8'),55.3(C-17'),51.9(C-18'),43.3(C-3),41.7(C-1'),
35.4(C-15'),23.5(C-4)。ESI-MS m/z:492.23[M+H]+。
The platelet aggregation inhibitory activity of 9 derivative of the present invention of embodiment
Using platelet aggregation instrument, (Beijing Puli gives birth to LBY-NJ2 four-way blood for the platelet aggregation-against experiment of compound
Condense instrument) measure.ADP is purchased from Sigma, and sodium citrate is purchased from company of Ke Miou chemical reagent Co., Ltd, physiological saline
Autogamy, Clopidogrel Hydrogensulfate is purchased from big incessanly Ninghai shore pharmaceutical Co. Ltd
Compound drug solution preparing:The compound for weighing certain mass is dissolved in a small amount of DMSO, pipette 1 μ L add 300 μ L go from
In sub- water, 37 DEG C of heating water baths, if being separated out without compound, the test for choosing the concentration as the experiment of external platelet aggregation-against is dense
Degree.If there is solid precipitation, plus aforesaid operations are repeated after DMSO diluted compounds solution, untill being separated out without compound.
The collection of blood specimen：Male scientific research rabbit fasting 24h, weighs, 5% chloral hydrate anesthesia, and neck arteries intubation takes blood,
109mmol/L liquor sodii citratises are with blood with 9:1 ratio anti-freezing, is collected in 10mL plastic centrifuge tubes.
It is prepared by blood plasma：The preparation of platelet rich plasma (PRP)：Being centrifuged at a temperature of 25-32 DEG C, rotating speed is 900 revs/min,
Time control took out (haemolysis such as occur to take a blood sample again) at 10 minutes after centrifuge stops naturally, will with pipettor
The PRP being centrifuged out is drawn onto in another test tube, is as far as possible all suctioned out PRP.The preparation of platelet poor plasma (PPP)：It will draw
The blood for crossing PRP centrifuges again, and rotating speed is 3500 revs/min, and for time control at 10 minutes or so, it was PPP to take out supernatant.Adjusted with PPP
Platelet count is 4~5 × 10 in whole PRP12Individual/L.Produce and start platelet aggregation measure after PRP after 30min, whole survey is lived
Process was completed in 3 hours.
Experimentation：Platelet aggregation test is carried out according to Bom turbidimetrys：300 μ L PPP, 1 μ L are added in blank tube
Toward 3 μ L ADP (0.2mmol/L) are added in cuvette after DMSO, 37 DEG C of constant temperature 5min, PPP zeroing, measure and record maximum gather
Collection rate.
Add 300 μ LPRP in measure pipe, be separately added into the μ L of each generation test sample product 1, after 37 DEG C of constant temperature 5min, PPP zeroings toward than
3 μ L ADP (0.2mmol/L) are added in color cup, measures and records maximum aggregation rate.Compared with physiological saline (NS).Calculate
L-Arginine (Aggregation Inhibition Rate, AIR).
Experimental result：
(1) inhibiting rate of different structure compound is contrasted, works as R1When substituting for phenyl, it can also be shown even if concentration is relatively low
Certain inhibiting rate, and R1When substituting for methyl, chlorine etc., inhibitory activity is weaker.R11- benzyls can be improved for bulky group substitution
The activity of the external platelet aggregation-against of base -6- first boc methyl tetrahydro isoquinoline derivatives, this conclusion and area of computer aided medicine
The result of thing design is consistent.
(2) nitrogen-atoms is modified with beneficial to enhancing activity, wherein, acetyl group modification is better than p-nitrophenyl second with amino acid modified
Acyl group is modified, and the modification of p-nitrophenyl acetyl group is better than benzyl modification.During computer simulation compound matches with pharmacophore, the part
Carbonyl and hydrogen bond receptor characteristic matching therein, have preferable confirmation with the Activity Results of experiment.
(3) Clopidogrel Hydrogensulfate does not show inhibitory action when concentration is 199 μm of ol/L, and compound 1~4 is in concentration
Inhibitory action is shown to platelet aggregation during less than 199 μm of ol/L；Clopidogrel Hydrogensulfate presses down when concentration is 598 μm of ol/L
Rate processed is 23.4%, and compound 2 is in 60 μm of ol/L with regard to that can show similar inhibiting rate therewith, and compound 1 is in 350 μm of ol/L
When show 97.5% inhibiting rate.All these phenomenons can show that 1- benzyl -6- first boc methyls tetrahydroisoquinoline derives
Thing shows good inhibiting effect to external hematoblastic aggregation.
Claims (4)
- A kind of 1. 1- benzyls -6- first boc methyl tetrahydro isoquinoline derivatives, it is characterised in that its be a kind of 1- substituted benzyls - N- alkyl (acyl group) -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydro isoquinoline derivatives, the derivative is structural formula Compound as shown in formula I：R1For C1-C10Alkyl, benzyl, C1-C10Alkyl acyl, C6-C12Aryl-acyl；R2=H, halogen.
- 2. a kind of 1- benzyls -6- first boc methyl tetrahydro isoquinoline derivatives, it is characterised in that the derivative is：(1) 1- [(1,1 '-xenyl) -4- methyl] -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydroisoquinolines, structure Formula is(2) 1- [(1,1 '-xenyl) -4- methyl]-N- acetyl group -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydrochysenes are different Quinoline, structural formula are(3) 1- [(1,1 '-xenyl) -4- methyl]-N- [(4 '-nitro) phenylacetyl group] -6- first boc methyl -7- methoxyl groups - 1,2,3,4- tetrahydroisoquinoline, structural formula are(4) 1- [(1,1 '-xenyl) -4- methyl]-N- (Boc- glycine aminoacyl) -6- first boc methyl -7- methoxyl group -1, 2,3,4- tetrahydroisoquinolines, structural formula are
- 3. a kind of preparation method of the 1- benzyl -6- first boc methyl tetrahydro isoquinoline derivatives described in claim 1 or 2, its It is characterised by, step is as follows：(1) in molar ratio 1:0~1.2 will contain R2The felbinac of substituent to methoxyphenethylamine hydrochloride with adding reactor In, acetonitrile as solvents, in the presence of HBTU and triethylamine, 15~60min of normal-temperature reaction, the amide derivatives substituted；(2) using benzenethiol as raw material, toluene is solvent, adds 1~1.4eq, 110 DEG C of back flow reactions of metallic sodium, then it is added dropwise 1~ 1.5eq methyl chloroacetates react 1~2h generation 2- benzene methyl thioglycolates；Then it is added dropwise 1.1 under the conditions of -10 DEG C of ice salt bath~ 1.3eq sulfonic acid chlorides react 1~2h generation chloro- 2- benzene methyl thioglycolates of alkylating reagent 2-；The acid amides that step (1) obtains is spread out Biology is dissolved in anhydrous methylene chloride, nitrogen charging gas shielded, and 1mmol is pressed under stirring at normal temperature:0.2mL ratio is slowly added dropwise anhydrous four Tin chloride solution, it is added dropwise, addition 1~1.25eq alkylating reagent normal-temperature reactions, 10~20min is obtained after stirring 10~20min To the methyl substituted amide derivatives of benzene sulfydryl methoxy carbonyl；(3) amide derivatives that step (2) obtains are dissolved in ethanol, by 1mmol:0.5~1.5g ratio adds Raney's nickel, Under nitrogen protection, stirring at normal temperature reacts 2~4h, obtains the methyl substituted amide derivatives of methoxy carbonyl；(4) amide derivatives for obtaining step (3) are by 1mmol:5mL ratio is dissolved in POCl3,95~115 DEG C of backflows 2~5h is reacted, vacuum rotary steam removes POCl3, by 1mmol:5mL ratio adds dichloromethane, and deionization is added under ice bath Water, after adjusting pH value to alkalescence, dichloromethane extraction, organic phase anhydrous sodium sulfate drying filters, and vacuum rotary steam obtains solid；Will Ring-closure reaction crude product is dissolved in dichloromethane, by 1mmol:5mL ratio adds methanol, and ice bath stirring is lower to add 1~2eq boron Sodium hydride, 1~2h of reaction obtain 1- substituted benzyl -6- first boc methyl -7- methoxyl groups -1,2,3,4- tetrahydroisoquinolines；(5) amino of 1- substituted benzyl -6- first boc methyl -7- methoxyl group -1,2,3,4- tetrahydro isoquinoline derivatives is distinguished It is alkylated and is acylated modification.
- 4. the 1- benzyl -6- first boc methyls tetrahydro isoquinoline derivative described in claim 1 or 2 is used to prepare treatment thrombus medicine Thing.
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