TW419476B - Preparation process of 1-chlorocarbonyl-4-piperidinopiperidine pr hydrochloride thereof - Google Patents
Preparation process of 1-chlorocarbonyl-4-piperidinopiperidine pr hydrochloride thereof Download PDFInfo
- Publication number
- TW419476B TW419476B TW087105000A TW87105000A TW419476B TW 419476 B TW419476 B TW 419476B TW 087105000 A TW087105000 A TW 087105000A TW 87105000 A TW87105000 A TW 87105000A TW 419476 B TW419476 B TW 419476B
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- TW
- Taiwan
- Prior art keywords
- hydrochloride
- following formula
- piperidinylpiperidine
- piperidinopiperidine
- represented
- Prior art date
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 17
- YDNSNQRKIINKPV-UHFFFAOYSA-N 4-piperidin-1-ylpiperidine-1-carbonyl chloride Chemical compound C1CN(C(=O)Cl)CCC1N1CCCCC1 YDNSNQRKIINKPV-UHFFFAOYSA-N 0.000 title description 2
- 238000002360 preparation method Methods 0.000 title description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- AKZWRTCWNXHHFR-PDIZUQLASA-N [(3S)-oxolan-3-yl] N-[(2S,3S)-4-[(5S)-5-benzyl-3-[(2R)-2-carbamoyloxy-2,3-dihydro-1H-inden-1-yl]-4-oxo-3H-pyrrol-5-yl]-3-hydroxy-1-phenylbutan-2-yl]carbamate Chemical compound NC(=O)O[C@@H]1Cc2ccccc2C1C1C=N[C@](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CCOC2)(Cc2ccccc2)C1=O AKZWRTCWNXHHFR-PDIZUQLASA-N 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000011049 filling Methods 0.000 claims description 6
- SZOYGDIBISWPMG-UHFFFAOYSA-N 4-piperidin-1-ylpiperidine-1-carboxamide Chemical compound C1CN(C(=O)N)CCC1N1CCCCC1 SZOYGDIBISWPMG-UHFFFAOYSA-N 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 4
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 4
- XDJWZONZDVNKDU-UHFFFAOYSA-N 1314-24-5 Chemical compound O=POP=O XDJWZONZDVNKDU-UHFFFAOYSA-N 0.000 claims description 3
- 244000025254 Cannabis sativa Species 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- VSAISIQCTGDGPU-UHFFFAOYSA-N phosphorus trioxide Inorganic materials O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 claims description 3
- OBCUTHMOOONNBS-UHFFFAOYSA-N phosphorus pentafluoride Chemical compound FP(F)(F)(F)F OBCUTHMOOONNBS-UHFFFAOYSA-N 0.000 claims description 2
- PCTMTFRHKVHKIS-BMFZQQSSSA-N (1s,3r,4e,6e,8e,10e,12e,14e,16e,18s,19r,20r,21s,25r,27r,30r,31r,33s,35r,37s,38r)-3-[(2r,3s,4s,5s,6r)-4-amino-3,5-dihydroxy-6-methyloxan-2-yl]oxy-19,25,27,30,31,33,35,37-octahydroxy-18,20,21-trimethyl-23-oxo-22,39-dioxabicyclo[33.3.1]nonatriaconta-4,6,8,10 Chemical compound C1C=C2C[C@@H](OS(O)(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2.O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 PCTMTFRHKVHKIS-BMFZQQSSSA-N 0.000 claims 1
- PVPBBTJXIKFICP-UHFFFAOYSA-N (7-aminophenothiazin-3-ylidene)azanium;chloride Chemical compound [Cl-].C1=CC(=[NH2+])C=C2SC3=CC(N)=CC=C3N=C21 PVPBBTJXIKFICP-UHFFFAOYSA-N 0.000 claims 1
- 230000002079 cooperative effect Effects 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- QDVBKXJMLILLLB-UHFFFAOYSA-N 1,4'-bipiperidine Chemical compound C1CCCCN1C1CCNCC1 QDVBKXJMLILLLB-UHFFFAOYSA-N 0.000 abstract description 9
- VBXXNCHZAMNCBX-UHFFFAOYSA-N 4-piperidin-1-ylpiperidine-1-carbonyl chloride;hydrochloride Chemical compound Cl.C1CN(C(=O)Cl)CCC1N1CCCCC1 VBXXNCHZAMNCBX-UHFFFAOYSA-N 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract 1
- 150000004820 halides Chemical class 0.000 abstract 1
- 239000007789 gas Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- -1 Carbon carbonyl-4-piperidinylpiperidine Chemical compound 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YRGWEBSOFIGCAC-UHFFFAOYSA-N C1CNC(=C=O)CC1N1CCCCC1 Chemical compound C1CNC(=C=O)CC1N1CCCCC1 YRGWEBSOFIGCAC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- KUUVQVSHGLHAKZ-UHFFFAOYSA-N thionine Chemical compound C=1C=CC=CSC=CC=1 KUUVQVSHGLHAKZ-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RGOIBUJVHSLBOA-UHFFFAOYSA-N 1-piperidin-2-ylpiperidine Chemical compound C1CCCCN1C1NCCCC1 RGOIBUJVHSLBOA-UHFFFAOYSA-N 0.000 description 1
- PMNCFNQTQOLKQP-UHFFFAOYSA-N 4-piperidin-1-ylpyridine hydrochloride Chemical compound Cl.N1(CCCCC1)C1=CC=NC=C1 PMNCFNQTQOLKQP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- BXTPDVUPAKXURS-UHFFFAOYSA-J [OH-].[Re+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[Re+4].[OH-].[OH-].[OH-] BXTPDVUPAKXURS-UHFFFAOYSA-J 0.000 description 1
- 150000001343 alkyl silanes Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- RLECCBFNWDXKPK-UHFFFAOYSA-N bis(trimethylsilyl)sulfide Chemical compound C[Si](C)(C)S[Si](C)(C)C RLECCBFNWDXKPK-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 231100000086 high toxicity Toxicity 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
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
A7 B7 經濟部中决標準局負工消费合作社印製 五、發明説明（ 技術領域 衣發明係有關一種製造氣羰基_4_哌啶基哌啶或其鹽 酸鹽之新顆方法’該化合物爲作爲醯胺類之重要中間物且 可用於醫藥領域等。 背景技術 卜氣羰基-4-哌啶基哌啶及其鹽酸鹽爲醯胺類之重要中, 間物且廣泛用於醫藥領域等。 此種1-氯羰基-4-哌啶基哌啶或其鹽酸鹽之製造方法爲 已知’例如包括使4-哌啶基哌啶與光氣二聚物（TcF)反應， 遽除過量之光氣二聚物而得丨_氣羰基_4_哌啶基哌啶鹽酸 鹽’接著若需要’以弱鹼如碳酸氫鈉或碳酸鉀水溶液處理 該壁酸鹽之方法（S. Sawada, Chem. Pharm. Bull·, 39，1446 (1991))。 但上述方法中，由於光氣二聚物具顯著高毒性，其運輪 極度*5:限且須在特定地區於特定裝置中使用，因而難以量 產氟致基-4-略咬基CF泉咬及其鹽酸鹽。此外，以鹽酸鹽沉 殿之化合物呈瓊膠狀且須花費長時間以完全過濾光氣·二聚 物’因此化合物在曝露至光氣二聚物時具高潛在危險。再 者’為此殿之1 -氯羰基_4-旅咬基展咬之鹽酸鹽以弱驗之水 溶液處理時，邵份鹽酸鹽溶於水溶液中並水解而不轉化成 卜氣羰基-4-哌啶基哌啶。因此上述方法產量低。 因此本發明之一目的係提供一種以高產率、高度安全且 易操作地製造1 -氣羰基_4_哌啶基哌啶或其鹽酸鹽之方法。 -4- 表錄尺度適用中賴家樣準（CNS ) Μ規格（2 297公楚） I-:~~τ-----¾------11 (請先閱讀背面之注意事項再填窍本頁) A7. A7.
B7 五、發明説明（2 ). 發明揭示 鑑於前述環境，本發明人朝達上述目的而進行廣泛研究 ，結果發現使4-旅啶基味啶三烷基矽烷化，使所得化合物 與二氧化碳氣體反應再與亞硫醯氣等反應並視需要以強鹼 處理，而可以高產率、高度安全且簡單地獲得1 -氣羰基-4-11 底喊基喊症或其鹽酸鹽，而完成本發明。 . 本發明可以下列反應圖表示： 三烷基矽烷基自化物 (步驟1) \ 1 二氧化碳氣體 N — S i ~ R * -> / U (步驟2)' (2) --i - I I - i ^ϋ. I l^- I - 分 i (請先閱讀背面之注意事項再填艿本頁) 經濟部中央標华局員工消费合作社印製
三氣化磷等 (步驟3)
COCf *HC 強驗 (步驟4” -5- 本紙張尺度適用中國國家標準（CNS ) A4規格（2!OX 297公f ) A7 五、發明説明（3
-COCf -6 其中R1，R2及R3爲相同t 」或不同且各代表直鏈或分支C 院基。 詳言之，本發明提供_種_ ^ . 備式（4)所示之丨_氣羰基_4_ 旅咬基㈣酸酸或式(5)所示之卜氣裂基-4-㈣基喊咬 心万法，包括(步驟1)使式⑴所示之4_哌啶基哌啶與三烷 基矽烷卣化物反應而得式（2)所示之4_哌啶基哌啶三烷基 矽烷’（步騾2)使所彳于化合物與二氧化碳氣體反應形成式〇) 所·;Π 4-喊呢基喊咬基三烷基矽烷基胺甲酸酯衍生物，使 所得衍生物與一或多種選自亞硫醯氣 '三氣化磷、五氣化 磷、草醯氣及磷醯三氣之物質反應，而得式（4)所示之！_ 氣羰基-4-哌啶基哌啶鹽酸鹽，再視需要以強鹼處理所得鹽 酸鹽。 實施本發明之最佳模式 隨後依步驟順序説明本發明方法。 (1)步驟1 欲與4-哌啶基哌啶反應之三烷基矽烷卣化物具有鍵結至 3個烷基及一個自原子之矽原子。烷基實例包含直鏈或分 支CU6烷基。三個烷基各可爲相同或不同。特定實例包含 甲基、乙基、正丙基 '異丙基、正丁基、異丁基、第二丁 基 '第三丁基、正戊基、異戊基、第二戊基、第二戊基及 -6- 本纸張尺度適用中國國家標* ( CNS ) A4規格（210X 297公釐）
If - m tj n I- - ϋ < 艮.一„ 丁 • -ό (請先閱讀背面之注意事項再填巧本頁} 經濟部中央標準局員工消費合作社印袈 Γ 419476 Α7 ________ Β7 J~^ --- 五、發明説明（4 ) ~ 環戊基。本發明中，以cw烷基特佳。南原子實例包含氣 、漠及續，以氣特佳。 “ 於適宜溶劑如二氣甲少充 '笨或乙猜中，分別溶解三貌基 矽烷画化物及4-哌啶基哌啶。所得溶液之一若需要可攪拌 同時在室溫或更低溫下於其中逐漸滴加另一溶液’而使其 反應。再繼續攪拌30分鐘至6小時，得4_哌啶基哌啶基三. 烷基矽烷（2)。較好例如在氮氣中進行反應。此外，較好三 烷基矽烷齒化物添加量（莫耳比例）大於4_哌啶基哌啶。 (2) 步驟2 步驟1所得溶液若需要予以攪拌同時將二氧化碳氣體吹 入落液中，而形成4-哌啶基哌啶三烷基矽烷基胺甲酸酯衍 生物（3)。較好二氧化碳氣體在室溫及大氣壓下以3〇分鐘至 6小時内，以4-哌啶基哌啶2倍量（莫耳比例）吹入溶液中^ (3) 步驟3 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填芎本頁) 於步戰2所得溶液中’在室溫或更低溫下，滴加選自亞 硫醯氣、三氣化磷、五氣化磷、磷醯三氣及草醯氣之—或 多種物質。滴加完成後’繼續攪拌約1至48小時a然後過 滤反應混合物以移除剩餘之4_旅啶基喊啶鹽酸鹽，因而於 渡液中得本發明之1 _氣羰基·4_喻啶基哌啶鹽酸鹽。此時反 應較好例如在氮氣中進行。較好添加與三烷基矽烷基卤化 物等昼（莫耳比例）之亞臨酿氯等。所得鹽酸鹽以水洗、乾 燥、濃縮並以本技藝本身已知之方式再結晶，由而得高純 度之i-氣羰基-4-哌啶基哌啶鹽酸鹽（4)。 本紙張尺&制CNS )鐵格（2丨以297公 一 - 五、發明説明（5 ) ~—~· (4)步驟4 步驟3中所得之濾液添加至強鹼水溶液中。本文可用之 強鹼實例包含氫氧化鈉、氫氧化鉀 '氫氧化麫、氫氧化鋇 、氫氧化鎂及氫氧化銨=> 此種強鹼之濃度並無特別限制， 但較好爲0.5至50 wt%，以1至30 wt%尤佳。藉此處理， 得到於有機層中之1-氣羰基-4-哌啶基哌啶。所得產物以水 洗、乾燥、濃縮及依本技藝本身已知之方法再結晶，而得 向產率高純度之1-氣羰基-4-哌啶基哌啶（5)。本發明中，上 述步驟1至4可於步驟1之反應器中進行，其與習知方法 相較可得產率改良。 或者，當意欲特佳之1-氣羰基_4_哌啶基哌啶（呈游離態） 之合成時，可於步驟3中存在有鹼性物質如三乙胺作爲氣 化氫清除劑。 實例 本發明隨後將以實例更詳細説明，惟需了解本發明不限 於下列實例。 實例1 1-氣羰基-4-哌啶基哌啶（1-5)之合成 經濟部中央標準局負工消资合作社印44 ----Μ-----^------,1Τ (請先閒請背面之注意事項再填艿本頁) 於3 00毫升二氣曱烷中，溶解2〇毫升（158毫莫耳）三甲 基矽烷基氣。所得溶液在冰冷卻及氮氣中攪拌同時於1小 時内逐漸滴加溶於1〇〇毫升二氣甲烷中之22克（131毫莫耳 )4-哌啶基哌啶（1 _丨）溶液。所得混合物在室溫攪拌1小時， 而得含4-喊咬基喊基三甲基矽燒（卜2)之溶液。携拌所得溶 液同時以2小時内吹入1大氣壓力之二氧化碳氣體5.9升 (262毫莫耳），得含肛哌啶基哌啶基三甲基矽烷基胺曱酸酯 _________ -8- 本紙if-尺度適用中國國家標举（CNS ) A4規格（21 〇 X 297公楚） A7 B7 五、發明説明（6 ) 衍生物（1-3)之溶液。於冰冷卻及氮氣中於所得溶液中以1〇 分鐘滴加1 1.5毫升（158毫莫耳）亞硫醯氯，接著在室溫攪 掉18小時，而得含1-氣羰基-4-喊啶基喊啶鹽酸鹽（ι_4)之 '谷液。過;慮落液並回收8 8克（3 3%)4-喊喊基成咬鹽酸鹽殘 留物。在冰冷卻下，濾液加至330毫升10%氫氧化鈉水溶 液中，接著分離之有機層以水洗，以無水硫酸鎂乾燥，再. 減恩濃縮。於濃縮液中添加異丙醚（50毫升）以溶解濃縮液 ’在於0 X：冷卻2小時。過濾移除沉澱物且殘留物於減壓 下濃縮。所得濃縮液自50毫升正己烷再結晶，得15克標 的化合物（】_5)。所得化合物具下列物理性質： 熔點：6 3.8 °C Hc】滴定：96.46% IR cm'1 ： 1 725 > 1409 NMR δ : 1.0-2.1 (10Η, m) » 2.1-3.4 (7H, m) » 4.1-4.6 (2H, m) 〇 工業利用性 本發明方法可以高產率、高度安全及易操作地製造高純 度疋丨_氣羰基-4-哌啶基嘁啶。 ^ I.¾------1T (請先閱讀背面之>i意事項再填寫本頁) M濟部中央標準局員工消费合作社印裝 適 度 尺 張 纸 i本 见 4 Λ N,s CN 一率 I榡 i釐 公
Claims (1)
- \3^ AS B8 C8 D8 申請專利範圍 I ~種以下式（4)表示之卜氣羰基-4.-略啶基喊啶鹽酸鹽： * HC f (j) 或下式（5)表示之1-氣羰基-4-哌啶基哌啶之製造方法： \-ZQC£ . (5) 其包括使下式（1)表示之4 -喊症基喊咬： ； 7-----於-- * (請先閲讀背面之注意事項再填寫本頁)與三烷基矽烷基齒化物反應，得下式（2)表示之4-哌啶基 喊啶基三烷基矽烷：經濟部中央椋準局員工消費合作社印裝 其中R1，R2及R3爲相同或不同且各獨立表示直鏈或分 支CI 烷基：使所得化合物與二氧化碳氣體反應，得下 式（3)表示之4-哌啶基哌啶基三烷基矽烷基'胺甲酸酯衍 生物： -10- 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 六、申請專利範圍 8 8 8 8 ABCD.D 3 11 其中R1，R2及R3具有前述相同.定義；使該衍生物與選 自亞硫醯氯、三氯化磷、五氣化磷、草醯氣及磷醯三氣· 之一或多種物質反應，及視需要與強鹼反應。 HI I 1- 1^1 - J ^ j ^^1 11 I—τ h 、τ (請先閏讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印策 -11 - 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）
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| Application Number | Priority Date | Filing Date | Title |
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| JP9093723A JP3046258B2 (ja) | 1997-04-11 | 1997-04-11 | １−クロロカルボニル−４−ピペリジノピペリジンまたはその塩酸塩の製造方法 |
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| TW419476B true TW419476B (en) | 2001-01-21 |
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| TW087105000A TW419476B (en) | 1997-04-11 | 1998-04-02 | Preparation process of 1-chlorocarbonyl-4-piperidinopiperidine pr hydrochloride thereof |
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| Country | Link |
|---|---|
| US (1) | US6147215A (zh) |
| EP (1) | EP0976733B1 (zh) |
| JP (1) | JP3046258B2 (zh) |
| CN (1) | CN1110479C (zh) |
| AT (1) | ATE232517T1 (zh) |
| AU (1) | AU723133B2 (zh) |
| BR (1) | BR9808105B1 (zh) |
| CA (1) | CA2286914C (zh) |
| DE (1) | DE69811358T2 (zh) |
| DK (1) | DK0976733T3 (zh) |
| EA (1) | EA001696B1 (zh) |
| ES (1) | ES2192765T3 (zh) |
| IL (1) | IL132077A (zh) |
| TW (1) | TW419476B (zh) |
| WO (1) | WO1998046568A1 (zh) |
| ZA (1) | ZA982960B (zh) |
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| JP3046258B2 (ja) | 1997-04-11 | 2000-05-29 | 株式会社ヤクルト本社 | １−クロロカルボニル−４−ピペリジノピペリジンまたはその塩酸塩の製造方法 |
| ES2430375T3 (es) * | 2005-02-08 | 2013-11-20 | Fermion Oy | Procedimiento para la producción de cloruro de [1,4']bipiperidinil-1'-carbonilo o su clorhidrato |
| US8546573B2 (en) * | 2009-11-18 | 2013-10-01 | Cadila Healthcare Limited | Process for the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperdino] carbonyloxy-camptothecin hydrochloride trihydrate |
| EP2519603A4 (en) | 2009-12-30 | 2013-06-26 | Schlumberger Services Petrol | METHOD FOR FLUID PISTON CONSOLIDATION IN A FLUID SYSTEM IN DRILLING APPLICATIONS |
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| JPS5540754A (en) * | 1978-09-19 | 1980-03-22 | Mitsubishi Electric Corp | Electrodeposition coating |
| JPS6019790A (ja) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| JPS6150984A (ja) * | 1984-07-05 | 1986-03-13 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| EP0555347A4 (en) * | 1990-10-31 | 1995-01-11 | Smithkline Beecham Corp | Substituted indolizino 1,2-b)quinolinones |
| JP3046258B2 (ja) | 1997-04-11 | 2000-05-29 | 株式会社ヤクルト本社 | １−クロロカルボニル−４−ピペリジノピペリジンまたはその塩酸塩の製造方法 |
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1997
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1998
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- 1998-03-31 CN CN98804019A patent/CN1110479C/zh not_active Expired - Fee Related
- 1998-03-31 DK DK98911123T patent/DK0976733T3/da active
- 1998-03-31 AT AT98911123T patent/ATE232517T1/de active
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- 1998-03-31 BR BRPI9808105-5A patent/BR9808105B1/pt not_active IP Right Cessation
- 1998-03-31 WO PCT/JP1998/001465 patent/WO1998046568A1/ja not_active Ceased
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Also Published As
| Publication number | Publication date |
|---|---|
| IL132077A0 (en) | 2001-03-19 |
| EP0976733A4 (en) | 2001-05-09 |
| DE69811358D1 (de) | 2003-03-20 |
| CA2286914A1 (en) | 1998-10-22 |
| WO1998046568A1 (en) | 1998-10-22 |
| CN1110479C (zh) | 2003-06-04 |
| EP0976733A1 (en) | 2000-02-02 |
| ATE232517T1 (de) | 2003-02-15 |
| JPH10287650A (ja) | 1998-10-27 |
| IL132077A (en) | 2002-11-10 |
| BR9808105A (pt) | 2000-03-08 |
| EP0976733B1 (en) | 2003-02-12 |
| ZA982960B (en) | 1998-10-09 |
| CN1252055A (zh) | 2000-05-03 |
| ES2192765T3 (es) | 2003-10-16 |
| AU723133B2 (en) | 2000-08-17 |
| US6147215A (en) | 2000-11-14 |
| BR9808105B1 (pt) | 2008-11-18 |
| EA199900926A1 (ru) | 2000-04-24 |
| AU6520698A (en) | 1998-11-11 |
| JP3046258B2 (ja) | 2000-05-29 |
| DE69811358T2 (de) | 2003-10-16 |
| EA001696B1 (ru) | 2001-06-25 |
| DK0976733T3 (da) | 2003-03-31 |
| CA2286914C (en) | 2005-07-26 |
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