CN103739540B - A kind of preparation method of bazedoxifene acetate intermediate - Google Patents
A kind of preparation method of bazedoxifene acetate intermediate Download PDFInfo
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- CN103739540B CN103739540B CN201410025111.8A CN201410025111A CN103739540B CN 103739540 B CN103739540 B CN 103739540B CN 201410025111 A CN201410025111 A CN 201410025111A CN 103739540 B CN103739540 B CN 103739540B
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- benzyloxy
- ethyl acetate
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- aniline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- OMZAMQFQZMUNTP-UHFFFAOYSA-N acetic acid;1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methylindol-5-ol Chemical compound CC(O)=O.C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 OMZAMQFQZMUNTP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 229960003713 bazedoxifene acetate Drugs 0.000 title claims abstract description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 31
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000000243 solution Substances 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 18
- 239000000706 filtrate Substances 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 16
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 13
- 238000010025 steaming Methods 0.000 claims description 12
- -1 after stirring Substances 0.000 claims description 10
- 229940072033 potash Drugs 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 235000015320 potassium carbonate Nutrition 0.000 claims description 10
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims 1
- 238000006197 hydroboration reaction Methods 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 abstract description 9
- IAPCKPXQFYWNDN-UHFFFAOYSA-N 2-bromo-1-(4-phenylmethoxyphenyl)ethanone Chemical compound C1=CC(C(=O)CBr)=CC=C1OCC1=CC=CC=C1 IAPCKPXQFYWNDN-UHFFFAOYSA-N 0.000 abstract description 7
- 238000005576 amination reaction Methods 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000013519 translation Methods 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- UCJGJABZCDBEDK-UHFFFAOYSA-N bazedoxifene Chemical compound C=1C=C(OCCN2CCCCCC2)C=CC=1CN1C2=CC=C(O)C=C2C(C)=C1C1=CC=C(O)C=C1 UCJGJABZCDBEDK-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 125000004185 ester group Chemical group 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- KDPAWGWELVVRCH-UHFFFAOYSA-M bromoacetate Chemical compound [O-]C(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-M 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- CGEOWJVEIAILOR-UHFFFAOYSA-N CCOC(COc1ccc(C=O)cc1)=O Chemical compound CCOC(COc1ccc(C=O)cc1)=O CGEOWJVEIAILOR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N NC(COc1ccc(C=O)cc1)=O Chemical compound NC(COc1ccc(C=O)cc1)=O FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- YVPJXVQVMWXILL-UHFFFAOYSA-N NCc(cc1)ccc1OCC(N)=O Chemical compound NCc(cc1)ccc1OCC(N)=O YVPJXVQVMWXILL-UHFFFAOYSA-N 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N acetaldehyde dimethyl acetal Natural products COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 229960000817 bazedoxifene Drugs 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037182 bone density Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a kind of preparation method of bazedoxifene acetate intermediate, described preparation method comprises the steps: that step Isosorbide-5-Nitrae-hydroxy benzaldehyde S01 and alkylates S02 condensation prepare 4-formoxyl phenoxy group analog derivative M01; Step 2,4-formoxyl phenoxy group analog derivative M01 and 4-benzyloxy-aniline S03 reduction amination are prepared N-(4-benzyl)-4-benzyloxy-aniline analog derivative M02; Step 3, N-(4-benzyl)-4-benzyloxy-aniline analog derivative M02 becomes ring preparation 5-benzyloxy-2-(4-(benzyloxy with 4 '-benzyloxy-2-brom-acetophenone S04) phenyl)-3-Methyl-1H-indole derivative M03.
Description
Technical field
The present invention relates to technical field of medicine synthesis, particularly, woman after the present invention relates to treatment or preventing menopauseThe intermediate synthetic method of female's osteoporosis agents bazedoxifene acetate.
Background technology
Bazedoxifene acetate (BazedoxifeneAcetate), chemical name is: 1-[4-(2-azacyclo-heptanAlkane-1-base-ethyoxyl)-benzyl]-2-(4-hydroxyl-phenyl)-3-Methyl-1H-indole-5-phenol acetate, its knotStructure is as follows:
Bazedoxifene acetate (BazedoxifeneAcetate) is Ligand company and Wyeth, AlmirallThe SERM class medicine of company's cooperative development, ratify first in April, 2009 in Europe,Commodity are called " Conbriza ".
Preclinical test data show, WAY 140424 regulates than other selective estrogen receptors known todayAgent (SERMs) has more target activity, is " the best of like product " so far. Clinical research shows, is increasingAdd bone density and reduce risk of bone fracture aspect, be significantly better than placebo, and WAY 140424 not stimulating uterus and breastGland cell, therefore can not cause endometrium and hyperplasia of mammary glands, and security is good. PMOPatient group is huge, and its harm causing should not be underestimated. WAY 140424, compared with similar drugs, has good medicineReason drug effect and security advantages, have wide market prospects.
At present the bazedoxifene acetate synthetic method of bibliographical information mainly contains following six kinds of methods, introduce respectively asUnder:
Method 1, with reference to CN1106383C, synthetic route is as follows. The weak point of this patent is:Synthetic route step is many; The upper substitution reaction productive rate of three-step reaction indoles N is low; LAH and NaH exist safety hiddenSuffer from; The impurity that the 6th step a word used for translation encircles modification reaction generation heptan is difficult for removing, and increases finished product purifying difficulty.
Method 2, with reference to CN100339371C, synthetic route is as follows. The weak point of this patent is:There is potential safety hazard in sodium borohydride and sodium hydrogen; A word used for translation ring in heptan is brought into from starting material, later reaction and dry if any tripWhile existence from alkali, all need inert gas or antioxidant protection.
Method 3, with reference to CN102690225A, synthetic route is as follows. The weak point of this patent is:A word used for translation ring in heptan starts to bring into from first step reaction, because the N on a word used for translation ring in heptan easily introduces new impurity; The last two steps reactionYield is low.
Method 4, with reference to US2012330008A1, synthetic route is as follows, in this patent, connect a word used for translation heptan ring andPalladium hydrocarbonize debenzylation two-step reaction is protected equally after exchanging. The weak point of this patent is: starting materialThe difficult buying of price.
Method 5, with reference to CN102395561A, synthetic route is as follows. The weak point of this patent is:The the 4th and the 5th step reaction yield is low.
Method 6, with reference to CN102395561A, synthetic route is as follows. The weak point of this patent is:Step is more.
In above method, synthetic method 3 starts a word used for translation ring in heptan to bring into from first step reaction, due to the N on a word used for translation ring in heptanEasily introduce new impurity, therefore the introducing of a word used for translation ring in heptan should not be placed on route first half. If a word used for translation ring in heptan can be existedIntroduce below and can avoid the side reaction on a word used for translation ring in heptan in intermediate preparation process, therefore we adopt on this basisWith CN1106383C, the method in CN102395561A, now prepare WAY 140424 intermediate:
Then prepare bazedoxifene acetate with this intermediate, the impurity shadow of having avoided the too early introducing of a word used for translation ring in heptan to bringRing, propose new preparation method simultaneously, improve yield, purity, so that acquisition is purer in next step reaction,The end-product that quality is more excellent.
Summary of the invention
The object of the invention is to disclose a kind of preparation method of bazedoxifene acetate intermediate of novelty.
Another object of the present invention is to disclose the intermediate using in bazedoxifene acetate preparation processCompound is in the application of preparing in bazedoxifene acetate.
Suc as formula a preparation method for the bazedoxifene acetate intermediate of M03,
Wherein R1For cyano group, amide groups, C1-C8Alkyl chain ester group, C1-C8Alkyl chain ketone group, with protecting groupAmino, halogen; It is characterized in that, said method comprising the steps of:
Step Isosorbide-5-Nitrae-hydroxy benzaldehyde S01 and alkylates S02 carry out condensation reaction and obtain under alkali condition4-formoxyl phenoxy group analog derivative M01,
Wherein R1As previously mentioned, R2For halogen, carboxylic acid halides;
This step alkali used be potash, sodium carbonate, sodium acid carbonate, NaOH, potassium hydroxide, triethylamine,Tri-n-butylamine; Reaction dissolvent is acetonitrile, propionitrile, ethyl acetate, propyl acetate, oxolane; Reaction temperature is0-70 DEG C, with 40-55 DEG C of optimum; Reaction time was 1-48 hour, with 4-7 hour optimum.
Step 2,4-formaldehyde phenyl alkyl ether M01 and 4-benzyloxy-aniline S03 carry out reduction amination and obtainN-(4-benzyl)-4-benzyloxy-aniline analog derivative M02,
This step reducing agent used is sodium triacetoxy borohydride or sodium borohydride; Reaction temperature is 0-70DEG C, with 30-35 DEG C of optimum; Reaction dissolvent is C1-C4Alcohols, oxolane, carrene, toluene or twoToluene; The mol ratio of 4-formaldehyde phenyl alkyl ether M01,4-benzyloxy-aniline S03 and reducing agent is 1:1:1～10,Wherein the ratio of reducing agent is with 2～3 optimums; Reaction time was 1-48 hour, with 3-6 hour optimum.
Step 3, N-(4-benzyl)-4-benzyloxy-aniline analog derivative M02 and 4 '-benzyloxy-2-Brom-acetophenone S04 carries out annulation and obtains 5-benzyloxy-2-(4-(benzyloxy under alkali condition) phenyl)-3-Methyl-1H-indole derivative M03,
This step alkali used be potash, sodium carbonate, sodium acid carbonate, NaOH, potassium hydroxide, triethylamine,Tri-n-butylamine; Solvent for use be DMF, DMA, toluene, dimethylbenzene orDimethyl sulfoxide (DMSO); Reaction temperature is 30-150 DEG C, with 100-130 DEG C of optimum; Reaction time is 1-48 hour,With 3-6 hour optimum.
Preferably, wherein,
Described in step 1, alkali is potash, sodium carbonate, sodium acid carbonate, NaOH, and reaction dissolvent is acetonitrile, tetrahydrochyseneFurans;
Described in step 2, reducing agent is sodium borohydride, and reaction dissolvent is C1-C4Alcohols;
Described in step 3, alkali is NaOH, triethylamine, tri-n-butylamine, reaction dissolvent be DMF,DMA.
R described in step 11For cyano group, amide groups, C1-C8Alkyl chain ester group, halogen; R2For fluorine, chlorine, bromine, iodine.It is preferred,
Described in step 1, reaction temperature is 40-55 DEG C; Reaction time is 4-7 hour, and described alkali is potash, reactionSolvent is acetonitrile, described R1For C1-C8Alkyl chain ester group, R2For bromine;
Described in step 2, reaction temperature is 30-35 DEG C, and the reaction time is 3-6 hour, and described reducing agent is sodium borohydride,Reaction dissolvent is ethanol,
Described in step 3, reaction temperature is 100-130 DEG C, and the reaction time is 3-6 hour, and described alkali is triethylamine, anti-Answering solvent is DMF.
Described R1For C1-C8Alkyl chain ester group, wherein R1For being ethyl acetate, R2For bromine;
Most preferred, preparation method of the present invention is as follows:
4-(formoxyl phenoxy group) preparation of-ethyl acetate
In 500ml there-necked flask, add parahydroxyben-zaldehyde (24.4g, 0.2mol), 2-bromoacetate(33.4g, 0.2mol) and potash (55.2g, 0.4mol), then add 300ml acetonitrile, at 50 DEG CStirring reaction 5h. After cool to room temperature, filter away insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing 200mlCarrene dissolves, and washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, must produceProduct;
N-(4-(ethyl acetate ether) benzyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g, 0.15mol) and 4-(firstAcyl group phenoxy group)-ethyl acetate (31.2g, 0.15mol), after stirring, solution is cooled to 0-5 DEG C,Add sodium borohydride (14.0g, 0.37mol) in batches, added rear reactant liquor and naturally risen to room temperature, 25 DEG C are stirredMix reaction 4h. Reaction finishes rear solution and is cooled to 0-5 DEG C, in solution, slowly adds the 100ml aqueous solution, addsAdd rear 0-5 DEG C stirring reaction 2 hours, revolve and evaporate most of ethanol, water is extracted with carrene,Merging organic phase washes 3 with water and washes, and anhydrous magnesium sulfate drying filters, and filtrate revolving steamed to obtain crude product, after being dried, must produceProduct;
1-(4-(ethyl acetate ether) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-The preparation of Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(ethyl acetate ether) benzene firstBase)-4-benzyloxy-aniline (19.6g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol)With 5.7g triethylamine, be stirred and heated to 120 DEG C of reactions 6 hours. After finishing, reaction is cooled to 0-5 DEG C to be poured intoIn 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product.M03 compound of the present invention is further introduced a word used for translation ring in heptan by conventional synthetic method, then gets rid of benzyloxyBase obtains WAY 140424, as CN1106383C, and the following methods in CN102395561A:
Advantage of the present invention is as follows:
The present invention and above-mentioned CN1106383C, the intermediate preparation method in CN102395561A patent compares,Advantage of the present invention is as follows:
The impurity effect of having avoided the too early introducing of a word used for translation ring in heptan to bring proposes new preparation method simultaneously, improves and receivesRate and purity, to obtain the end-product of high-purity and high yield in next step reaction.
Below data are proved by experiment:
The intermediate M03 of gained can introduce a word used for translation ring in heptan by conventional synthetic method, then gets rid of benzyloxy and obtainsTo WAY 140424.
For proving the advantage of the inventive method, spy provides following detection data:
Intermediate yield prepared by the embodiment of the present invention 1 method is high, and purity is high, and impurity 1-3 content is low.
Detailed description of the invention
Can conduct further description the present invention by the following examples, but scope of the present invention is notBe confined to following embodiment.
Embodiment 1
4-(formoxyl phenoxy group) preparation of-ethyl acetate
In 500ml there-necked flask, add parahydroxyben-zaldehyde (24.4g, 0.2mol), 2-bromoacetate(33.4g, 0.2mol) and potash (55.2g, 0.4mol), then add 300ml acetonitrile, at 50 DEG CStirring reaction 5h. After cool to room temperature, filter away insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing 200mlCarrene dissolves, and washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, must produceProduct 37.98g, productive rate 91.3%.
N-(4-(ethyl acetate ether) benzyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g, 0.15mol) and 4-(firstAcyl group phenoxy group)-ethyl acetate (31.2g, 0.15mol), after stirring, solution is cooled to 0-5 DEG C,Add sodium borohydride (14.0g, 0.37mol) in batches, added rear reactant liquor and naturally risen to room temperature, 25 DEG C are stirredMix reaction 4h. Reaction finishes rear solution and is cooled to 0-5 DEG C, in solution, slowly adds the 100ml aqueous solution, addsAdd rear 0-5 DEG C stirring reaction 2 hours, revolve and evaporate most of ethanol, water is extracted with carrene,Merging organic phase washes 3 with water and washes, and anhydrous magnesium sulfate drying filters, and filtrate revolving steamed to obtain crude product, after being dried, must produceProduct 36.04g, productive rate 75.2%.
1-(4-(ethyl acetate ether) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-The preparation of Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(ethyl acetate ether) benzene firstBase)-4-benzyloxy-aniline (19.6g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol)With 5.7g triethylamine, be stirred and heated to 120 DEG C of reactions 6 hours. After finishing, reaction is cooled to 0-5 DEG C to be poured intoIn 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product20.56g, yield 67.2%.
Embodiment 2
2-(4-formoxyl phenoxy group) preparation of-acetonitrile
In 500ml there-necked flask, add parahydroxyben-zaldehyde (24.4g, 0.2mol), 2-bromoacetonitrile (24g,0.2mol) and potash (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction at 50 DEG C5h. After cool to room temperature, filter away insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing 200ml dichloromethaneAlkane dissolves, and washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 28.72g,Productive rate 89.1%.
N-(4-(acetonitrile ether) benzyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g, 0.15mol) and 2-(4-Formoxyl phenoxy group)-acetonitrile (24.15g, 0.15mol), after stirring, solution is cooled to 0-5 DEG C,Add sodium borohydride (14.0g, 0.37mol) in batches, added rear reactant liquor and naturally risen to room temperature, 25 DEG C are stirredMix reaction 4h. Reaction finishes rear solution and is cooled to 0-5 DEG C, in solution, slowly adds the 100ml aqueous solution, addsAdd rear 0-5 DEG C stirring reaction 2 hours, revolve and evaporate most of ethanol, water is extracted with carrene,Merging organic phase washes 3 with water and washes, and anhydrous magnesium sulfate drying filters, and filtrate revolving steamed to obtain crude product, after being dried, must produceProduct 35.18g, productive rate 68.1%.
1-(4-(acetonitrile ether) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-methylThe preparation of-1H-indoles
In 100ml single port bottle, add 20mlN, dinethylformamide, N-(4-(acetonitrile ether) benzyl)-4-benzyloxy-aniline (17.2g, 0.05mol), 4 '-benzyloxy-2-brom-acetophenone (16.0g, 0.05mol)With 5.7g triethylamine, be stirred and heated to 120 DEG C of reactions 6 hours. After finishing, reaction is cooled to 0-5 DEG C to be poured intoIn 100ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product17.73g, yield 62.8%.
Embodiment 3
Amide groups
4-(formoxyl phenoxy group) preparation of-acetamide
In 500ml there-necked flask, add parahydroxyben-zaldehyde (24.4g, 0.2mol), 2-acetbromamide (27.6g,0.2mol) and potash (55.2g, 0.4mol), then add 300ml acetonitrile, stirring reaction at 50 DEG C5h. After cool to room temperature, filter away insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing 200ml dichloromethaneAlkane dissolves, and washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, obtains product 27.31g,Productive rate 76.3%.
N-(4-(acetamide) benzyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 200ml ethanol, 4-benzyloxy-aniline (19.9g, 0.10mol) and 4-(firstAcyl group phenoxy group)-acetamide (14.3g, 0.08mol), after stirring, solution is cooled to 0-5 DEG C, pointCriticize and add sodium borohydride (7.57g, 0.20mol), added rear reactant liquor and naturally risen to room temperature, 25 DEG C of stirringsReaction 4h. Reaction finishes rear solution and is cooled to 0-5 DEG C, in solution, slowly adds the 100ml aqueous solution, addsComplete rear 0-5 DEG C of stirring reaction 2 hours, revolves and evaporates most of ethanol, water extracted with carrene,Merging organic phase washes 3 with water and washes, and anhydrous magnesium sulfate drying filters, and filtrate revolving steamed to obtain crude product, after being dried, must produceProduct 13.10g, productive rate 45.2%.
1-(4-(acetamide) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-methyl isophthalic acid H-The preparation of indoles
In 50ml single port bottle, add 12mlN, dinethylformamide, N-(4-(acetamide) benzyl)-4-Benzyloxy-aniline (10.9g, 0.03mol), 4 '-benzyloxy-2-brom-acetophenone (9.6g, 0.03mol)With 3.42g triethylamine, be stirred and heated to 120 DEG C of reactions 6 hours. After finishing, reaction is cooled to 0-5 DEG C to pour intoIn 50ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to such an extent that produceProduct 10.70g, yield 61.2%.
Embodiment 4
4-(formoxyl phenoxy group) preparation of-methyl acetate
In 500ml there-necked flask, add parahydroxyben-zaldehyde (24.4g, 0.2mol), 2-methyl bromoacetate(30.6g, 0.2mol) and potash (55.2g, 0.4mol), then add 300ml acetonitrile, at 50 DEG CStirring reaction 5h. After cool to room temperature, filter away insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing 200mlCarrene dissolves, and washes 3 times, and anhydrous magnesium sulfate drying, filters, and filtrate is revolved steaming, after crude product is dry, must produceProduct 34.96g, productive rate 90.1%.
N-(4-(methyl acetate ether) benzyl) preparation of-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 4-benzyloxy-aniline (29.8g, 0.15mol) and 4-(firstAcyl group phenoxy group)-methyl acetate (29.1g, 0.15mol), after stirring, solution is cooled to 0-5 DEG C,Add sodium borohydride (14.0g, 0.37mol) in batches, added rear reactant liquor and naturally risen to room temperature, 25 DEG C are stirredMix reaction 4h. Reaction finishes rear solution and is cooled to 0-5 DEG C, in solution, slowly adds the 100ml aqueous solution, addsAdd rear 0-5 DEG C stirring reaction 2 hours, revolve and evaporate most of ethanol, water is extracted with carrene,Merging organic phase washes 3 with water and washes, and anhydrous magnesium sulfate drying filters, and filtrate revolving steamed to obtain crude product, after being dried, must produceProduct 37.02g, productive rate 65.4%.
1-(4-(methyl acetate ether) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-The preparation of Methyl-1H-indole
In 100ml single port bottle, add 36mlN, dinethylformamide, N-(4-(methyl acetate ether) benzene firstBase)-4-benzyloxy-aniline (33.9g, 0.09mol), 4 '-benzyloxy-2-brom-acetophenone (28.8g, 0.09mol)With 10.3g triethylamine, be stirred and heated to 120 DEG C of reactions 6 hours. After finishing, reaction is cooled to 0-5 DEG C to pour intoIn 150ml frozen water, stir 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to such an extent that produceProduct 33.94g, yield 62.8%.
Claims (1)
1. a preparation method for bazedoxifene acetate intermediate, step is as follows:
The preparation of 4-(formoxyl phenoxy group)-ethyl acetate
In 500ml there-necked flask, add 24.4g parahydroxyben-zaldehyde, 33.4g2-bromoacetate and55.2g potash, then adds 300ml acetonitrile, and stirring reaction 5h at 50 DEG C, after cool to room temperature, filtersRemove insoluble matter, filtrate sylvite is revolved to steaming, residual molten thing dissolves with 200ml carrene, washes 3 times, anhydrousDried over mgso, filters, and filtrate is revolved steaming, after crude product is dry, obtains 4-(formoxyl phenoxy group)-ethyl acetate;
The preparation of N-(4-(ethyl acetate ether) benzyl)-4-benzyloxy-aniline
In 500ml there-necked flask, add 300ml ethanol, 29.8g4-benzyloxy-aniline and 31.2g4-(formoxylPhenoxy group)-ethyl acetate, after stirring, solution is cooled to 0-5 DEG C, adds 14.0g hydroboration in batchesSodium, has added rear reactant liquor and has naturally risen to room temperature, 25 DEG C of stirring reaction 4h, and reaction finishes rear solution and is cooled to0-5 DEG C slowly adds the 100ml aqueous solution in solution, has added rear 0-5 DEG C stirring reaction 2 hours, revolvesEvaporate most of ethanol, water is extracted with carrene, merge organic phase and wash with water 3 times, anhydrous sulphurAcid magnesium is dry, filters, and filtrate revolving steamed to obtain crude product, after being dried, obtains N-(4-(ethyl acetate ether) benzyl)-4-benzyloxy-aniline;
1-(4-(ethyl acetate ether) benzyl)-5-benzyloxy-2-(4-(benzyloxy) phenyl)-3-The preparation of Methyl-1H-indole
In 100ml single port bottle, add 20mlN, dinethylformamide, 19.6gN-(4-(ethyl acetate ether)Benzyl)-4-benzyloxy-aniline, 16.0g4 '-benzyloxy-2-brom-acetophenone and 5.7g triethylamine, stirMix and be heated to 120 DEG C of reactions 6 hours, after reaction finishes, be cooled to 0-5 DEG C to be poured in 100ml frozen water, stirMix 1 hour, solution is extracted with ethyl acetate, and after washing and drying, crude product is dried to obtain product.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998402A (en) * | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
| CN1326347A (en) * | 1998-05-15 | 2001-12-12 | 美国家用产品公司 | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
| WO2011022596A2 (en) * | 2009-08-21 | 2011-02-24 | Dr. Reddy's Laboratories Ltd. | Preparation of bazedoxifene and its salts |
| CN102395561A (en) * | 2009-04-13 | 2012-03-28 | 桑多斯股份公司 | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
| CN102690225A (en) * | 2012-04-11 | 2012-09-26 | 南京友杰医药科技有限公司 | New synthetic method of bazedoxifene |
-
2014
- 2014-01-20 CN CN201410025111.8A patent/CN103739540B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5998402A (en) * | 1996-04-19 | 1999-12-07 | American Home Products Corporation | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indoles as estrogenic agents |
| CN1326347A (en) * | 1998-05-15 | 2001-12-12 | 美国家用产品公司 | 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole in combination with estrogens |
| CN102395561A (en) * | 2009-04-13 | 2012-03-28 | 桑多斯股份公司 | Processes for the synthesis of bazedoxifene acetate and intermediates thereof |
| WO2011022596A2 (en) * | 2009-08-21 | 2011-02-24 | Dr. Reddy's Laboratories Ltd. | Preparation of bazedoxifene and its salts |
| CN102690225A (en) * | 2012-04-11 | 2012-09-26 | 南京友杰医药科技有限公司 | New synthetic method of bazedoxifene |
Non-Patent Citations (1)
| Title |
|---|
| Design, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole Estrogens;Chris P. Miller，等;《Journal of Medicinal Chemistry》;20010425;第44卷(第11期);第1654-1657页，特别第1655页方案1 * |
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