CN107098868B - A kind of preparation method of paricalcitol intermediate - Google Patents
A kind of preparation method of paricalcitol intermediate Download PDFInfo
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- CN107098868B CN107098868B CN201710296264.XA CN201710296264A CN107098868B CN 107098868 B CN107098868 B CN 107098868B CN 201710296264 A CN201710296264 A CN 201710296264A CN 107098868 B CN107098868 B CN 107098868B
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- 229960000987 paricalcitol Drugs 0.000 title abstract description 15
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 title abstract description 15
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 238000000034 method Methods 0.000 claims abstract description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005575 aldol reaction Methods 0.000 claims abstract description 6
- -1 methyl sulphur Acyl chloride Chemical class 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 9
- 230000008901 benefit Effects 0.000 abstract description 4
- 230000003287 optical effect Effects 0.000 abstract description 3
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000000000 cycloalkoxy group Chemical group 0.000 description 2
- 125000005366 cycloalkylthio group Chemical group 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 125000001072 heteroaryl group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- BPKAHTKRCLCHEA-FOPGHSPUSA-N 19-Nor-1-α,25-dihydroxyvitamin D2 Chemical compound C1([C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](C=C[C@H](C)C(C)(C)O)C)=CC=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-FOPGHSPUSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 1
- 229910001148 Al-Li alloy Inorganic materials 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical compound [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940052212 zemplar Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium compounds
- C07F9/5442—Aromatic phosphonium compounds (P-C aromatic linkage)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of preparation methods of paricalcitol intermediate, the preparation method of especially a kind of intermediate (shown in formula (I)) for synthesizing paricalcitol (II), the method obtains chiral intermediate shown in formula (V) by the asymmetric aldol reaction of chipal compounds shown in formula (IV) and acetone, then by reduction, it is halogenated and reacted with triphenyl phosphorus shown in formula (I) for synthesizing the intermediate of paricalcitol.The advantages that this method has reaction condition mild, easy to operate, optical purity height and cheap synthesis cost is suitable for large-scale production.
Description
The application is that Chinese Patent Application No. is 201310046160.5, entitled " among a kind of paricalcitol
The preparation method of body ", the divisional application for the Chinese invention patent application that the applying date is on 2 5th, 2013.
Technical field
The present invention relates to a kind of preparation methods of paricalcitol intermediate.
Background technique
Paricalcitol (paricalcitol, II), trade name Zemplar is Abbott Laboratories from winconsin
Research Foundation secures permission and the synthesis of vitamin d analogues developed, be obtained in 1998 FDA approval for preventing and controlling
Treat the drug of adult secondary hyperparathyroidism (SHPT).
Formula (I) compound represented is to synthesize the important intermediate of paricalcitol.Synthetic route as follows is existing
The synthetic method of published formula (I) compound represented.
The synthetic route (Tetrahedron 1992,48,5151) of compound (I)
In said synthesis route, (S)-Roche methyl esters (shown in Formula X) is starting material, however, (S)-Roche methyl esters
It is expensive, and be not easy largely to buy, thus using existing synthetic method largely synthesize formula (I) compound represented there is also
It is many difficult and insufficient, it is necessary to developing low-cost and the method for being suitable for extensive synthesis formula (I) compound represented.
Summary of the invention
For paricalcitol intermediate shown in existing formula (I) synthesis technology there are the shortcomings that, the present invention provides
The variation route of paricalcitol intermediate shown in one synthesis formula (I), the route are with chiral auxiliary (III) cheap and easy to get
Starting material reacts to obtain shown in Formula V by chipal compounds shown in Formula IV with the asymmetric aldol condensation (Aldol) of acetone
Chiral intermediate, then by reduction, it is halogenated and reacted with triphenyl phosphorus shown in Formulas I for synthesizing paricalcitol
Intermediate.The advantages that this method has reaction condition mild, easy to operate, optical purity height and cheap synthesis cost is suitable for big
Large-scale production.
One aspect of the present invention provides formula (V) compound represented and preparation method thereof, and compound shown in formula (V) is to be used for
Paricalcitol intermediate shown in synthesis formula (I),
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably R are benzyl.
Formula (V) compound represented can be made according to following preparation method: chipal compounds and acetone shown in formula (IV)
Asymmetric aldol reaction obtain formula (V) compound represented,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl.
In yet other embodiments, the R is benzyl.
Asymmetric aldol reaction is a kind of method for commonly preparing chiral alcohol, and for details, reference can be made to documents:
J.Am.Chem.Soc.1979,101,6120.
Chipal compounds shown in formula (IV) can be reacted to obtain by chiral auxiliary (III) with propionyl chloride or propionic acid,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably phenyl.
Another aspect of the present invention provides a kind of preparation method of formula (I) compound represented,
It includes that the asymmetric aldol reaction of chipal compounds shown in formula (IV) and acetone obtains changing shown in formula (V)
The step of closing object,
Wherein, X is halogen, preferably chlorine, bromine, iodine, and R is substituted or non-substituted C1-10Alkyl or phenyl.
In a preferred embodiment, the X is iodine, and the R is benzyl.
In a preferred embodiment of the present invention, the preparation method of formula (I) compound represented still further comprises
In reducing agent under effect, formula (V) compound represented is reduced the step of obtaining formula (VI) compound represented, and described goes back
Former agent is sodium borohydride, lithium borohydride, potassium borohydride or lithium aluminium hydride reduction, preferably sodium borohydride,
Wherein defined in R formula (V) compound represented.
In another preferred embodiment of the present invention, the preparation method of formula (I) compound represented is also into one
Step includes that formula (V) compound represented obtains formula (IX) compound represented, then in reducing agent under effect, formula after hydrolysis
(IX) compound represented is reduced the step of obtaining formula (VI) compound represented, and the reducing agent is lithium aluminium hydride reduction, boron
Sodium hydride, lithium borohydride or potassium borohydride, preferably lithium aluminium hydride reduction,
Wherein defined in R formula (V) compound represented.
After obtained formula (VI) compound represented, further prepared shown in formula (I) by formula (VI) compound represented
Compound can be carried out by method known in the state of the art, in a preferred embodiment of the present invention, using Tetrahedron
The route provided in 1992,48,5151 carries out, specifically, being obtained shown in formula (VII) by what is reacted with to methylsufonyl chloride
Compound, formula (VIII) compound represented, chemical combination shown in formula (VIII) are obtained after formula (VII) compound represented is halogenated
Compound shown in formula (I) is obtained after the reaction of object triphenyl phosphorus,
In an especially preferred embodiment, X is iodine in compound shown in formula (I), is the chemical combination as shown in (Ia)
Object, the synthetic route that the present invention provides the compound as shown in (Ia) are as follows:
Specifically, this method includes the following steps:
1) chiral auxiliary compound shown in formula (IIIa) reacts to obtain the compound of formula (VIa) with propionyl chloride；
2) the asymmetric aldol reaction of compound (VIa) and acetone obtain chiral intermediate shown in formula (Va) (dr >
99:1)；
3) compound (Va) obtains chipal compounds shown in formula (VI) after sodium borohydride reduction；
4) what compound (VI) was reacted with to methylsufonyl chloride obtains formula (VII) compound represented；
5) compound (VII) obtains formula (VIIIa) compound represented after reacting with lithium iodide；
6) compound (VIIIa) obtains formula (Ia) compound represented after reacting with triphenyl phosphorus.
The invention also discloses the preparation methods of formula (VI) compound represented, can be by chirality shown in formula (V)
The sodium borohydride reduction of mesosome obtains,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably benzyl.
Alternatively, chiral intermediate shown in formula (V) obtains formula (IX) compound represented, compound (IX) warp after hydrolysis
Formula (VI) compound represented is obtained after Lithium aluminum hydride reduction,
Wherein, R is substituted or non-substituted C1-10Alkyl or phenyl, preferably benzyl.
The preparation method of paricalcitol intermediate shown in formula (I) of the present invention has easy to operate, reaction item
The features such as part is mild, and optical purity is high, and combined coefficient is high, and synthesis cost is cheap, is suitble to industrialized production has significant society
Benefit and economic benefit.
Term used in the present invention has following meaning in addition to having opposite statement:
" alkyl " refers to the aliphatic hydrocarbon group of saturation, and straight chain and branched group including 1 to 10 carbon atom preferably include 1
To 6 carbon atoms.Non-limiting embodiment include but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group,
Tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propyl, 2,2- dimethyl propyl, 1- ethyl propyl,
2- methyl butyl, 3- methyl butyl, n-hexyl, 1- Ethyl-2-Methyl propyl, 1,1,2- thmethylpropyl, 1,1- dimethyl butyrate
Base, 1,2- dimethylbutyl, 2,2- dimethylbutyl, 1,3- dimethylbutyl, 2- ethyl-butyl, 2- methyl amyl, 3- methyl
Amyl, 4- methyl amyl, 2,3- dimethylbutyl etc..Alkyl can be substituted or unsubstituted, when substituted, substituent group
It can be substituted on any workable tie point, preferably one or more following groups, independently selected from alkyl, alkene
Base, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, aryl,
Heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group, oxo.
" aryl " refers to 6 to 10 yuan of full carbon monocycles or fused polycycle (rings of namely shared adjacent carbon atoms pair) group, tool
There are polycyclic (i.e. its ring for the having phase adjacency pair carbon atom) group of the pi-electron system of conjugation, such as phenyl and naphthalene.Aryl can be with
Be it is substituted or unsubstituted, when substituted, substituent group is preferably one or more following groups, independently selected from alkyl,
Alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano, naphthenic base, Heterocyclylalkyl, virtue
Base, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio group.
Abbreviations table:
| Abbreviation | Full name |
| Bn | Benzyl |
| Ph | Phenyl |
| Ts | To Methyl benzenesulfonyl base |
Specific embodiment
The present invention is explained in detail below with reference to specific example so that this hair is more fully understood in those skilled in the art
Bright, specific example is only used to illustrate the technical scheme of the present invention, and does not limit the present invention in any way.
Embodiment 1: prepare compound Va
Compound IIIa (177g is purchased from Jiangsu Sen Xuan medication chemistry company) is dissolved in 3L methylene chloride, cools to 0 DEG C,
Triethylamine (162g) and 4-dimethylaminopyridine (12g) is added, propionyl chloride is added dropwise, and (101g reaches auspicious fine chemicals purchased from Shanghai
Co., Ltd), 0 DEG C is reacted 1 hour, and water quenching reaction is added, and methylene chloride phase is collected in liquid separation, and anhydrous sodium sulfate dries, filters,
It is concentrated to give 220g compound IVa, is directly used in next step.
Compound IVa (220g) is dissolved in 2.5L methylene chloride, 0 DEG C of dropwise addition titanium tetrachloride (186g), stirs 15 points
Diisopropyl ethyl amine (133.4g) is added dropwise after clock, is cooled to -20 DEG C, titanium tetrachloride (186g) and acetone is successively added dropwise
(109g) reacts 2 hours.Add water quenching reaction, methylene chloride phase is collected in liquid separation, and anhydrous sodium sulfate is dried, filtered, is concentrated to give
250g solid product Va, two step yields 90%.
Va:1HMNR(400MHz,CDCl3): 7.23-7.34 (m, 5H), 4.72 (m, 1H), 4.12-4.19 (m, 2H),
3.93-3.96 (dd, 1H, J=6.4,14.4Hz), 3.39 (s, 1H), 3.32-3.36 (dd, 1H, J=3.6,13.2Hz),
2.71-2.76 (dd, 1H, J=9.2,14.0Hz), 1.34 (s, 3H), 1.24 (s, 3H), 1.22-1.24 (d, 3H, J=
7.2Hz)。
Embodiment 2: prepare compound VI
Compound Va (200g) is dissolved in 3.6L tetrahydrofuran and 1L water, is added sodium borohydride (148g), it is anti-at 20 DEG C
It answers 24 hours, is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate is dry.Concentration, crude product are dense through short silica gel column purification
Contract to obtain 75g compound VI, yield 92%.
VI:1HMNR(400MHz,CDCl3):3.68-3.76(m,2H),1.80-1.84(m,1H),1.27(s,3H),1.19
(s,3H),0.87(d,3H)。
Embodiment 3: prepare compound VI
Compound Va (120g) is dissolved in 2L tetrahydrofuran, and 500ml water is added, and system cools to 0 DEG C, and 30% peroxide is added
Change hydrogen (313ml) and Lithium hydroxide monohydrate (35g), stirring, 0 DEG C is reacted 6 hours, and methyl tertiary butyl ether(MTBE) extracts organic phase, water phase
With dilute hydrochloric acid tune pH value=2, extraction is proposed with ethyl acetate, extract liquor is dried, filtered with anhydrous sodium sulfate, is concentrated to give 50g chemical combination
Object IX yield: 91%.
IX:1HMNR(400MHz,CDCl3): 2.54-2.59 (m, 1H), 1.32 (s, 3H), 1.25-1.27 (m, 6H).
Lithium aluminium hydride reduction (36g) is dissolved in 3L anhydrous tetrahydro furan, cools to -20 DEG C, the four of compound IX (50g) are added
Hydrogen tetrahydrofuran solution (100ml) after 1 hour, is warming up to 20 DEG C naturally, reacts 15 hours at 20 DEG C.Excessive hydrogenation is quenched with water
Aluminium lithium is added dropwise 20%HCl and adjusts pH=2, is extracted with ethyl acetate, and combined ethyl acetate phase, anhydrous sodium sulfate dries, filters,
Concentration, obtains 39g compound VI, yield: 88%.
VI:1HMNR(400MHz,CDCl3):3.68-3.76(m,2H),1.80-1.84(m,1H),1.27(s,3H),1.19
(s,3H),0.87(d,3H)。
Embodiment 4: prepare compound Ia
Compound VI (37g) is dissolved in 350mL pyridine, cools to -15 DEG C, be added p-methyl benzene sulfonic chloride (65.5g,
0.345mol), it reacted 12 hours for -15 DEG C.Reaction is quenched with water, methyl tertiary butyl ether(MTBE) extraction merges methyl tertiary butyl ether(MTBE) phase,
15% hydrochloric acid is washed till acidity, and anhydrous sodium sulfate is dry, and concentration obtains 80g compound VII, 99.5%ee, yield: 93%.
VII:1HMNR:7.79(d,2H),7.35(d,2H),4.24(m,1H),3.93(m,1H),2.45(s,3H),1.85
(m,1H),1.19(s,3H),1.12(s,3H),0.96(d,3H)。
Compound VII (57g) is dissolved in 400mL anhydrous tetrahydro furan, is added anhydrous lithium iodide (35g), is warming up to 65
DEG C, it reacts 1 hour, reaction is quenched with water, is extracted with ethyl acetate, merge organic phase, anhydrous sodium sulfate dries, filters, and is concentrated
Obtain 45g compound VIIIa, yield: 93%.
VIIIa:1H-NMR(400MHz,CDCl3):3.68(dd,1H),2.92(dd,1H),1.86(m,1H),1.26(s,
3H),1.17(s,3H),1.11(d,3H)。
Compound VIIIa (41g) is dissolved in 1L acetonitrile, is added triphenylphosphine (330g), nitrogen protection is heated to reflux down
Reaction 48 hours.It is concentrated under reduced pressure, 600mL anhydrous ether is added, stir, filtering obtains 75g solid product Ia, yield after drying:
85%.
Ia:1HNMR(400MHz,CDCl3):7.97-7.69(m,15H),4.47(m,1H),2.88-2.78(m,1H),
2.11(m,1H),1.37(s,3H),1.28(s,3H),0.53(d,3H)。
Due to describing the present invention according to its specific embodiment, certain modifications and equivalent variations are for being proficient in this neck
The technical staff in domain is obvious and is included within the scope of the invention.
Claims (5)
1. a kind of method for preparing compound shown in formula (VI), which is characterized in that the method includes the chiralitys as shown in formula (IV)
The asymmetric aldol reaction of compound and acetone obtains the step of compound shown in formula (V),
Further include the steps that compound shown in formula (V) is reduced to obtain compound shown in formula (VI),
The reducing agent of the reduction reaction is selected from sodium borohydride, lithium borohydride, potassium borohydride or lithium aluminium hydride reduction；
Or compound shown in formula (V) obtains compound shown in formula (IX) after hydrolysis, and then under reducing agent effect, formula (IX) institute
Show that compound is reduced the step of obtaining compound shown in formula (VI),
The reducing agent is selected from lithium aluminium hydride reduction, sodium borohydride, lithium borohydride or potassium borohydride；Wherein R is benzyl.
2. the method as described in claim 1, which is characterized in that compound shown in formula (V) is reduced to obtain formula (VI) shownization
The reducing agent of the step of closing object, the reduction reaction is selected from sodium borohydride.
3. the method as described in claim 1, which is characterized in that compound shown in formula (V) is obtained after hydrolysis shown in formula (IX)
Compound, then under reducing agent effect, compound shown in formula (IX) is reduced the step of obtaining compound shown in formula (VI), institute
It states reducing agent and is selected from lithium aluminium hydride reduction.
4. the method as described in claim 1, which is characterized in that the method also includes compound and propionyl shown in formula (III)
Chlorine or propionic acid react the step of obtaining chiral intermediate (IV),
Wherein, it is defined in R such as claim 1.
5. method as claimed in claim 4, which is characterized in that the method includes compound shown in formula (VI) and to methyl sulphur
Acyl chloride reaction obtains compound shown in formula (VII), and chemical combination shown in formula (VIII) is obtained after compound shown in formula (VII) is halogenated
Object, compound shown in formula (VIII) obtain compound shown in formula (I) after reacting with triphenyl phosphorus,
Wherein defined in R such as claim 1；
X is selected from chlorine, bromine or iodine.
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| Preparation of Chiral Oxazolidin-2-ones and Vicinal Amino Alcohols;James M. Takacs, et al;《J. Org. Chem.》;19980319;第63卷(第8期);第2742-2748页 |
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