US20010051729A1 - Novel reduction compositions and processes for making the same - Google Patents
Novel reduction compositions and processes for making the same Download PDFInfo
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- US20010051729A1 US20010051729A1 US09/262,093 US26209399A US2001051729A1 US 20010051729 A1 US20010051729 A1 US 20010051729A1 US 26209399 A US26209399 A US 26209399A US 2001051729 A1 US2001051729 A1 US 2001051729A1
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- Prior art keywords
- slurry
- hydride
- additive
- lithium
- reduction
- Prior art date
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- 230000009467 reduction Effects 0.000 title claims abstract description 71
- 239000000203 mixture Substances 0.000 title claims abstract description 70
- 238000000034 method Methods 0.000 title claims description 31
- 230000008569 process Effects 0.000 title claims description 28
- 239000000654 additive Substances 0.000 claims abstract description 43
- 150000004678 hydrides Chemical class 0.000 claims abstract description 33
- 230000000996 additive effect Effects 0.000 claims abstract description 28
- 239000000758 substrate Substances 0.000 claims abstract description 27
- 239000002879 Lewis base Substances 0.000 claims abstract description 22
- 150000007527 lewis bases Chemical class 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000004215 Carbon black (E152) Substances 0.000 claims abstract description 11
- 229930195733 hydrocarbon Natural products 0.000 claims abstract description 11
- 150000002430 hydrocarbons Chemical class 0.000 claims abstract description 11
- 230000001603 reducing effect Effects 0.000 claims abstract description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 158
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 136
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 96
- -1 lithium alkoxides Chemical class 0.000 claims description 92
- 239000002002 slurry Substances 0.000 claims description 47
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 24
- 229910052744 lithium Inorganic materials 0.000 claims description 18
- VLLPYAIUEKEIRQ-AAEUAGOBSA-N ethyl (3s,4r)-4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate Chemical group C1C(=O)N(C)C(=O)[C@@H](C(=O)OCC)[C@@H]1C1=CC=C(F)C=C1 VLLPYAIUEKEIRQ-AAEUAGOBSA-N 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 150000001408 amides Chemical class 0.000 claims description 7
- 238000011065 in-situ storage Methods 0.000 claims description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 230000001133 acceleration Effects 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052782 aluminium Inorganic materials 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- MXRJHOMXFFBLFI-JQWIXIFHSA-N methyl (3s,4r)-4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate Chemical compound C1C(=O)N(C)C(=O)[C@@H](C(=O)OC)[C@@H]1C1=CC=C(F)C=C1 MXRJHOMXFFBLFI-JQWIXIFHSA-N 0.000 claims description 3
- UBZYKBZMAMTNKW-UHFFFAOYSA-J titanium tetrabromide Chemical compound Br[Ti](Br)(Br)Br UBZYKBZMAMTNKW-UHFFFAOYSA-J 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 230000001747 exhibiting effect Effects 0.000 claims 1
- 150000002642 lithium compounds Chemical class 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 238000006722 reduction reaction Methods 0.000 description 61
- 239000012280 lithium aluminium hydride Substances 0.000 description 60
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 238000006243 chemical reaction Methods 0.000 description 41
- 229910020828 NaAlH4 Inorganic materials 0.000 description 37
- 239000007787 solid Substances 0.000 description 28
- 229910052786 argon Inorganic materials 0.000 description 24
- 239000000047 product Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 238000001914 filtration Methods 0.000 description 13
- KYEACNNYFNZCST-UHFFFAOYSA-N 1-methylpyrrolidine-2,5-dione Chemical compound CN1C(=O)CCC1=O KYEACNNYFNZCST-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- 229920006362 Teflon® Polymers 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- CXRHUYYZISIIMT-AAEUAGOBSA-N [(3s,4r)-4-(4-fluorophenyl)-1-methylpiperidin-3-yl]methanol Chemical compound OC[C@@H]1CN(C)CC[C@H]1C1=CC=C(F)C=C1 CXRHUYYZISIIMT-AAEUAGOBSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 150000003949 imides Chemical class 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- VFJJNMLPRDRTCO-UHFFFAOYSA-N ethyl 1-methylpiperidine-3-carboxylate Chemical compound CCOC(=O)C1CCCN(C)C1 VFJJNMLPRDRTCO-UHFFFAOYSA-N 0.000 description 6
- 239000012535 impurity Substances 0.000 description 6
- ORMQZSGMNHLEQG-UHFFFAOYSA-N CN1C(=O)CCC1=O.CN1CCCC1 Chemical compound CN1C(=O)CCC1=O.CN1CCCC1 ORMQZSGMNHLEQG-UHFFFAOYSA-N 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 235000011089 carbon dioxide Nutrition 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 0 *OC(=O)C1C(=O)N(C)C(=O)CC1C1=CC=C(F)C=C1.CN1CCC(C2=CC=C(F)C=C2)C(CO)C1 Chemical compound *OC(=O)C1C(=O)N(C)C(=O)CC1C1=CC=C(F)C=C1.CN1CCC(C2=CC=C(F)C=C2)C(CO)C1 0.000 description 4
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 150000002118 epoxides Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 238000001665 trituration Methods 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009616 inductively coupled plasma Methods 0.000 description 3
- 229910000103 lithium hydride Inorganic materials 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229910010082 LiAlH Inorganic materials 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- MXRJHOMXFFBLFI-UHFFFAOYSA-N methyl 4-(4-fluorophenyl)-1-methyl-2,6-dioxopiperidine-3-carboxylate Chemical compound C1C(=O)N(C)C(=O)C(C(=O)OC)C1C1=CC=C(F)C=C1 MXRJHOMXFFBLFI-UHFFFAOYSA-N 0.000 description 2
- 150000002826 nitrites Chemical class 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- NXLACVVNHYIYJN-ZIAGYGMSSA-N (1r)-1-phenyl-n-[(1r)-1-phenylethyl]ethanamine Chemical compound C1([C@@H](C)N[C@H](C)C=2C=CC=CC=2)=CC=CC=C1 NXLACVVNHYIYJN-ZIAGYGMSSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- HVZCFAUOPSHFEQ-UHFFFAOYSA-N CC(=O)C1C(=O)N(C)C(=O)CC1C1=CC=C(F)C=C1.CN1CCC(C2=CC=C(F)C=C2)C(CO)C1 Chemical compound CC(=O)C1C(=O)N(C)C(=O)CC1C1=CC=C(F)C=C1.CN1CCC(C2=CC=C(F)C=C2)C(CO)C1 HVZCFAUOPSHFEQ-UHFFFAOYSA-N 0.000 description 1
- APWVIHYBWKYVNF-UHFFFAOYSA-N CC(=O)C1CCCN(C)C1.CN1CCCC(CO)C1 Chemical compound CC(=O)C1CCCN(C)C1.CN1CCCC(CO)C1 APWVIHYBWKYVNF-UHFFFAOYSA-N 0.000 description 1
- AVFZOVWCLRSYKC-UHFFFAOYSA-N CN1CCCC1 Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910020889 NaBH3 Inorganic materials 0.000 description 1
- 229910003074 TiCl4 Inorganic materials 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- PQLAYKMGZDUDLQ-UHFFFAOYSA-K aluminium bromide Chemical compound Br[Al](Br)Br PQLAYKMGZDUDLQ-UHFFFAOYSA-K 0.000 description 1
- 229910000091 aluminium hydride Inorganic materials 0.000 description 1
- 150000003931 anilides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000006259 organic additive Substances 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
-
- 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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
Definitions
- This invention relates to novel compositions for reduction of organic substrates, and processes for preparing and using the same.
- Lithium aluminum hydride (LiAlH 4 ) is a powerful reducing agent, soluble in organic solvents, and has found wide utility in organic synthesis.
- a wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitrites and imides.
- the expense of lithium aluminum hydride prevents its wider industrial employment.
- One method involves the metathesis of sodium aluminum hydride (NaAlH 4 )with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1).
- Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3).
- equations 1-3 There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.
- compositions prepared from an active hydride, an additive, and a Lewis base can provide a superior reducing system for organic substrates.
- a composition prepared from 60 mole % tetrahydrofuran as the Lewis base, 10 mole % lithium chloride as the additive, 10 mole % sodium aluminum hydride as the active hydride, and 20 mole % toluene can afford excellent yields in standard organic reductions.
- the compositions of the invention are non-pyrophoric and are more thermally stable than pure THF solutions of sodium aluminum hydride (NaAlH 4 ) or lithium aluminum hydride (LiAlH 4 ).
- novel compositions of the invention can be prepared by initially adding the Lewis base to the additive.
- the hydride species can then be added, optionally in the hydrocarbon solvent.
- the mixture can then be optionally heated to the reflux temperature (or less), typically from about thirty minutes to about four hours.
- the present invention also provides processes for the reduction of organic substrates using the compositions of the invention.
- active hydrides including metal hydrides such as sodium aluminum hydride, trisodium aluminum hexahydride, and the like and mixtures thereof can be employed as the active hydride component.
- useful additives include, but are not limited to, lithium chloride, lithium bromide, aluminum trichloride, titanium tetrachloride, titanium tetrabromide, lithium alkoxides, lithium alkoxides of chiral alcohols (such as menthol), lithium dialkylamides, lithium dialkyl amides of chiral amines (such as (+) bis-[(R)-1-phenethyl]amine), and the like and mixtures thereof.
- useful hydrocarbon solvents include, but are not limited to, pentane, hexane, heptane, cyclohexane, decane, toluene, xylenes, ethylbenzene, cumene, cymene, and the like and mixtures thereof.
- Lewis bases examples include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl t-butyl ether (MTBE), 1,2-diethoxyethane, 1,2-dimethoxyethane, triethylamine, tributylamine, N, N, N′, N′-tetramethylethylenediamine (TMEDA), diisopropylethylamine, and the like and mixtures thereof.
- TMEDA triethylamine
- Typical concentrations (mole %) of the components used to prepare the reducing composition of the invention are listed in the table below. COMPONENT MINIMUM MAXIMUM Lewis Base 45 80 Solvent 0 30 Additive 5 20 Hydride 5 20
- novel compositions of the invention can be prepared by initially adding the Lewis base to the additive.
- the hydride species can then be added, optionally in the hydrocarbon solvent.
- the mixture can then be optionally heated to the reflux temperature (or less) for a few hours, typically from about thirty minutes to about four hours.
- the novel composition is prepared by adding a slurry of sodium aluminum hydride/toluene to a slurry of lithium chloride/tetrahydrofuran. Because the addition is very exothermic, care should be taken. When using the specific reagents sodium aluminum hydride and lithium chloride, the reagents must be combined in a precise manner to result in reduction product yields comparable to that of lithium aluminum hydride. Otherwise, reduction product yields comparable to that of sodium aluminum hydride result.
- the composition of the invention is also unique as it is prepared from a slurry of sodium aluminum hydride in hydrocarbon solvent (i.e., about 80 weight percent (wt %) or less sodium aluminum hydride) and a minimal amount of tetrahydrofuran, in contrast to solid or damp cake forms of sodium aluminum hydride.
- the slurry can be a commercially available slurry of 40 wt % sodium aluminum hydride in toluene.
- a hydrocarbon solvent alone, such as toluene without a Lewis base, such as tetrahydrofuran, can hinder the preparation of this effective, novel composition.
- composition of the invention can include starting materials, counterion exchange products, complexes of starting materials and/or counterion exchange products, and mixtures thereof.
- the novel reduction composition of this invention can also be characterized by its particle size distribution.
- typical particle size distribution of a novel reduction composition in accordance with the invention prepared from 56.9 mole % tetrahydrofuran as the Lewis base, 15.7 mole % lithium chloride as the additive, 12.6 mole % sodium aluminum hydride as the active hydride, and 14.8 mole % toluene was determined on a Malvern MasterSizer.
- the mean diameter for the reduction composition is around 350 ⁇ m and the median is 400 ⁇ m.
- the particle size distribution of sodium aluminum hydride exhibits a mean diameter at 216 ⁇ m and a median at 200 ⁇ m.
- the particle size distribution of lithium chloride exhibits a mean diameter at 424 , ⁇ m and a median at 448 ⁇ m.
- the thermal behavior of the novel reduction composition was studied in an RSST (Reactive System Screening Tool) and found to be more thermally stable than 10 wt % LiAlH 4 /THF or 40 wt % NaAlH 4 .
- the LiAlH 4 /THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 130° C.
- a NaAlH 4 /THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 220° C.
- the organic compound to be reduced is added to the reduction composition of the invention under an inert atmosphere.
- the reduction composition can be added to the organic substrate, or the reduction composition and organic substrate added simultaneously.
- the reduction reaction proceeds under appropriate conditions at a temperature sufficient and for a time sufficient for the reduction reaction to proceed, generally at a temperature of about ambient to about the reflux temperature of the mixture for about one hour to about 24 hours.
- the reaction can be terminated by quenching the mixture, for example, by addition of water and aqueous NaOH and cooling. Work-up of the reduction reaction mixture and isolation of the reduced product can be accomplished using conventional procedures known in the art.
- compositions of the invention can be used for the reduction of a variety of organic compounds including without limitation aldehydes, ketones, esters, amides, epoxides, nitrites, and other imides.
- exemplary compounds which can be reduced in accordance with the invention include (+/ ⁇ ) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (to (+1-) trans 4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine), N-methylsuccinimide, ethyl 1-methylnipecotate, and the like.
- the inventors have found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives.
- reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives as described above.
- the additive lithium chloride could be mixed with sodium aluminum hydride in order to produce a resulting hydride composition that performs as well as lithium aluminum hydride alone.
- LiCl can be reacted with NaAlH 4 in stoichiometric amounts to form lithium aluminum hydride, which is then separated from the by-product, NaCl, prior to use.
- This metathesis reaction requires the addition of a catalyst, such as a small amount of LiAlH 4, to initiate the reaction, or alternatively a NaAlH 4 solution forming prestep.
- LiCl can be added in less than stoichiometric amounts, and without requiring LiAlH 4 as a catalyst, or a NaAlH 4 solution forming prestep.
- the order of addition of the additive is important. However, it is not currently believed that the order of addition of the additives is critical when using other starting materials, in which case it is currently believed that the additives can be added at various times during the entire reduction.
- LiAlH 4 Although reductions performed with LiAlH 4 provide better yields than when using NaAlH 4 (i.e., NaAlH 4 without additives may be less reactive in some cases), LiAlH 4 is much more expensive than NaAlH 4 . Reductions of functional groups, especially imides, employing NaAIH 4 in accordance with the invention, however, with the appropriate additives gave identical results as obtained when using the more costly commercial LiAlH 4 .
- the present invention also describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents.
- This aspect of the present invention overcomes prior difficulties associated with the commercial preparation of lithium aluminum hydride. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction of functional groups, especially imides. Unfiltered lithium aluminum hydride prepared from sodium aluminum hydride and lithium chloride, or unfiltered lithium or sodium aluminum hydride prepared from the elements can be used directly in subsequent reduction of the substrate. If required for yield improvement, other additives can be added to the sodium aluminum hydride. The resulting unfiltered, in situ-prepared hydride reducing agents are used directly for reduction of a substrate in an organic solvent.
- reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives. It is reported in the literature that commercial sodium aluminum hydride (NaAlH 4 ) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride. It was found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives.
- the additive lithium chloride
- sodium aluminum hydride could be mixed with sodium aluminum hydride in order to produce a resulting hydride that performed as well as sodium aluminum hydride with the additive, lithium aluminum hydride, or lithium aluminum hydride alone.
- LiCl can be reacted with NaAlH 4 in stoichiometric amounts to form lithium aluminum hydride (equation 1), which is then separated from the by-product, NaCl, prior to use.
- equation 1 lithium aluminum hydride
- NaCl sodium hydride
- LiCl can be added in less than stoichiometric amounts and the NaCl is not separated from the resulting hydride.
- inorganic or organic additives can be added to either reduction protocol to aid the reduction. These additives can be employed in 0.01 equivalents up to and including 5 equivalents.
- useful additives include, but are not limited to LiCl, HCl, LiBr, AlCl 3 , TiCl 4 , AlBr 3 , TiBr 4 , LiAlH 4 , NaBH 4 , LiBH 4 , LiBH(R) 3 , NaBH 3 (anilide), THF-BH 3 , LiAlH(OMe) 3 , LiAlH(O-t-Bu) 3 , NaAlH 2 (OC 2 H4OCH 3 ), AlH 3 ; ethers such as methyl t-butyl ether, dimethoxyethane, glymes; alcohols such as methanol, ethanol, isopropanol, t-butanol, ethereal alcohols and/or their corresponding
- a 500 ml., three-necked round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet.
- This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon.
- the flask was charged with 10.00 grams (0.237 mole) of anhydrous lithium chloride, and 70 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed.
- This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.
- a 500 ml., three-necked, jacketed, round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet.
- This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon.
- the flask was charged with 13.80 grams (0.327 mole) of anhydrous lithium chloride, and 97 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs.
- This slurry was prepared from 15.5 mole % lithium chloride, 56.8 mole % tetrahydrofuran, 10.9 mole % sodium aluminum hydride, and 16.9 mole % toluene.
- a 500 ml., three-necked round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet.
- This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon.
- the flask was charged with 10.00 grams (0.237 mole) of anhydrous lithium chloride, and 70 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed.
- This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.
- a 500 ml., three-necked, jacketed flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet.
- This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon.
- the flask was charged with tetrahydrofuran, 70 ml. This solution was stirred at 350 RPMs and cooled to 0° C. with a circulating chiller.
- the feed rate was adjusted to maintain the reaction temperature at 10-15° C. Total imide-ester feed time was 62 minutes. After the end of the feed, the reaction mixture was heated to 65° C. for two hours, then recooled to 0° C. Additional toluene, 85 ml., was added. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 9 ml., was then added dropwise. At the end of this feed, the reaction mixture was warmed to 65° C. The reaction mixture was stirred at 65° C.
- a 500 ml., four-necked, round bottom flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, a Teflon® stopper and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet.
- This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon.
- Lithium chloride 9.85 grams (2.64 equivalents, 232.36 mmole) was added. The flask was then charged with tetrahydroflran, 67 ml.
- the feed rate was adjusted to maintain the reaction temperature at 10-15° C. After the end of the feed, the 250 ml. flask was rinsed with additional toluene, 7 ml, and this was added to the addition funnel. The reaction mixture was heated to 75° C. for three hours, then recooled to 10° C. Additional toluene, 50 ml., was added. The speed of the agitator was increased to 500 RPMs. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 18 ml., was then added dropwise.
- reaction mixture was warmed to 65° C. for twenty minutes and the stirrer was slowed to 350 RPMs.
- the reaction mixture was then cooled to 400° C., then the solids were collected on a Buchner funnel.
- the solids were reslurried with toluene (2 ⁇ 31 ml.).
- the desired product was isolated by precipitation from the combined filtrates, washed, air dried, then dried in a vacuum desiccator overnight.
- LiCl (0.11 mol) in THF.
- LiCl can be added to the reactor prior to the addition of NaAlH 4 or after the addition of the substrate, (+/ ⁇ )trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione.
- (+/ ⁇ )trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C.
- reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to ⁇ 5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H 2 O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene.
- LiCl (0.11 mol) in THF.
- LiCl can be added to the reactor prior to the addition of NaAlH 4 or after the addition of the substrate.
- N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15° C.
- reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. The reaction is then cooled to ⁇ 5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C.
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Abstract
Description
- This application is a continuation-in-part application of commonly owned copending U.S. application Ser. No. 08/817,003, filed Mar. 31, 1997, the entire disclosure of which is hereby incorporated by reference, and is related to commonly owned provisional application Serial No. 60/001,857, filed Aug. 3, 1995 and claims the benefit of the earlier filing date of this application under 35 USC §119(e), and is also a continuation-in-part application of commonly owned U.S. application Ser. No. 09/051,813, filed Apr. 15, 1998, the entire disclosure of which is incorporated by reference, which is related to commonly owned copending provisional application Serail No. 60/026,552, filed Sep. 24, 1996, and claims the benefit of the earlier filing date of this application under 35 U.S.C. §119(e).
- This invention relates to novel compositions for reduction of organic substrates, and processes for preparing and using the same.
- There are a wide variety of reducing agents available for organic synthesis. For example, sodium borohydride, borane, lithium aluminum hydride and hydrogen are all employed to perform reductions industrially. Lithium aluminum hydride (LiAlH4) is a powerful reducing agent, soluble in organic solvents, and has found wide utility in organic synthesis. A wide variety of functional groups are reduced with this reagent, including aldehydes, ketones, esters, amides, epoxides, nitrites and imides. However, the expense of lithium aluminum hydride prevents its wider industrial employment.
- A variety of synthetic methods exist for the commercial preparation of lithium aluminum hydride. One method involves the metathesis of sodium aluminum hydride (NaAlH4)with lithium chloride to form lithium aluminum hydride and sodium chloride (equation 1). Another method is the hydrogenation of a mixture of lithium (or lithium hydride) and aluminum to generate lithium aluminum hydride (equations 2 and 3). There are several others variations of equations 1-3 as well as from aluminum chloride and alkali salts and hydrides (equations 4 and 5). It should be noted that preparations of lithium aluminum hydride are never targeted for the preparation of a mixed alkali aluminum hydride such as a mixture of lithium and sodium aluminum hydrides.
- LiCl+NaAlH4→LiAlH4+NaCl 1.
- Li+Al+2H2→LiAlH4 2.
- LiH+Al+3/2H2→LiAlH4 3.
- 4 NaH+AlCl3+LiCl→LiAlH4+NaCl 4.
- 4 LiH+AlCl3→LiAlH4+3NaCl 5.
- All of these preparations are typically conducted in an organic solvent, such as toluene, diethyl ether, or tetrahydrofuran. Also, at the conclusion of the reaction, the reaction mixture is laboriously filtered to remove the unreacted starting materials and/or by-product inorganic salts. These filtrations are time consuming, the equipment is capital intensive, and some of the lithium aluminum hydride product adheres to the solids, which reduces the yield. The solid by-products and starting materials are very hazardous and must be handled, recycled, and quenched very carefully.
- It has been discovered that a composition prepared from an active hydride, an additive, and a Lewis base, optionally in a hydrocarbon solvent, can provide a superior reducing system for organic substrates. For example, a composition prepared from 60 mole % tetrahydrofuran as the Lewis base, 10 mole % lithium chloride as the additive, 10 mole % sodium aluminum hydride as the active hydride, and 20 mole % toluene can afford excellent yields in standard organic reductions. In addition, the compositions of the invention are non-pyrophoric and are more thermally stable than pure THF solutions of sodium aluminum hydride (NaAlH4) or lithium aluminum hydride (LiAlH4).
- The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less), typically from about thirty minutes to about four hours.
- The present invention also provides processes for the reduction of organic substrates using the compositions of the invention.
- Various active hydrides, including metal hydrides such as sodium aluminum hydride, trisodium aluminum hexahydride, and the like and mixtures thereof can be employed as the active hydride component. Examples of useful additives include, but are not limited to, lithium chloride, lithium bromide, aluminum trichloride, titanium tetrachloride, titanium tetrabromide, lithium alkoxides, lithium alkoxides of chiral alcohols (such as menthol), lithium dialkylamides, lithium dialkyl amides of chiral amines (such as (+) bis-[(R)-1-phenethyl]amine), and the like and mixtures thereof. Examples of useful hydrocarbon solvents include, but are not limited to, pentane, hexane, heptane, cyclohexane, decane, toluene, xylenes, ethylbenzene, cumene, cymene, and the like and mixtures thereof. Examples of useful Lewis bases include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl t-butyl ether (MTBE), 1,2-diethoxyethane, 1,2-dimethoxyethane, triethylamine, tributylamine, N, N, N′, N′-tetramethylethylenediamine (TMEDA), diisopropylethylamine, and the like and mixtures thereof.
- Typical concentrations (mole %) of the components used to prepare the reducing composition of the invention are listed in the table below.
COMPONENT MINIMUM MAXIMUM Lewis Base 45 80 Solvent 0 30 Additive 5 20 Hydride 5 20 - The novel compositions of the invention can be prepared by initially adding the Lewis base to the additive. The hydride species can then be added, optionally in the hydrocarbon solvent. The mixture can then be optionally heated to the reflux temperature (or less) for a few hours, typically from about thirty minutes to about four hours.
- In one advantageous embodiment of the invention, the novel composition is prepared by adding a slurry of sodium aluminum hydride/toluene to a slurry of lithium chloride/tetrahydrofuran. Because the addition is very exothermic, care should be taken. When using the specific reagents sodium aluminum hydride and lithium chloride, the reagents must be combined in a precise manner to result in reduction product yields comparable to that of lithium aluminum hydride. Otherwise, reduction product yields comparable to that of sodium aluminum hydride result.
- When using sodium aluminum hydride as a starting material, the composition of the invention is also unique as it is prepared from a slurry of sodium aluminum hydride in hydrocarbon solvent (i.e., about 80 weight percent (wt %) or less sodium aluminum hydride) and a minimal amount of tetrahydrofuran, in contrast to solid or damp cake forms of sodium aluminum hydride. For example, the slurry can be a commercially available slurry of 40 wt % sodium aluminum hydride in toluene. The use of a hydrocarbon solvent alone, such as toluene, without a Lewis base, such as tetrahydrofuran, can hinder the preparation of this effective, novel composition.
- Although not wishing to be bound by any explanation of the invention, it is believed that the composition of the invention can include starting materials, counterion exchange products, complexes of starting materials and/or counterion exchange products, and mixtures thereof.
- The novel reduction composition of this invention can also be characterized by its particle size distribution. For example, typical particle size distribution of a novel reduction composition in accordance with the invention prepared from 56.9 mole % tetrahydrofuran as the Lewis base, 15.7 mole % lithium chloride as the additive, 12.6 mole % sodium aluminum hydride as the active hydride, and 14.8 mole % toluene was determined on a Malvern MasterSizer. The mean diameter for the reduction composition is around 350 μm and the median is 400 μm. By comparison, the particle size distribution of sodium aluminum hydride exhibits a mean diameter at 216 μm and a median at 200 μm. The particle size distribution of lithium chloride exhibits a mean diameter at 424 ,μm and a median at 448 μm.
- It has also been found that this same representative reduction composition slurry sample can be analyzed for sodium, lithium and aluminum by ICP (Inductively Coupled Plasma) and for chloride by wet titration. This data confirms the appropriate proportions of NaAlH4 and LiCl combined during the preparation of this novel reduction composition. This is especially important when the sodium aluminum hydride charge cannot be accurately determined, for example, on large scale. Example ICP and chloride analyses are represented below. Chloride analysis is faster and combined with a hydride content analysis, should confirm the ratio of NaAIH4 and LiCl.
Theoretical Lot# 10976 Lot# 11011 11.4% NaAlH4 10.9% by Na 11.0% by Na 11.5% by Al 11.7% by Al 9.8% LiCl 9.9% by Li 9.9% by Li 9.3% by Cl 9.2% by Cl - The thermal behavior of the novel reduction composition was studied in an RSST (Reactive System Screening Tool) and found to be more thermally stable than 10 wt % LiAlH4/THF or 40 wt % NaAlH4. The LiAlH4/THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 130° C. Likewise, a NaAlH4/THF solution was found to produce a runaway reaction represented by a rapid rate acceleration when heated above 220° C. Whereas a similar experiment with a novel reduction composition mixture prepared from 9.7 mole % NaAIH4, 16 mole % LiCl, 10.4 mole % toluene and 63.9 mole % THF showed a rate acceleration/runaway behavior only when heated above 300° C. These experiments demonstrate that the novel reduction composition formulation is safer and thus more stable than a 10 wt % LiAlH4/THF solution as well as a 40 wt % NaAIH4/THF solution.
- In use, the organic compound to be reduced is added to the reduction composition of the invention under an inert atmosphere. Alternatively, the reduction composition can be added to the organic substrate, or the reduction composition and organic substrate added simultaneously. The reduction reaction proceeds under appropriate conditions at a temperature sufficient and for a time sufficient for the reduction reaction to proceed, generally at a temperature of about ambient to about the reflux temperature of the mixture for about one hour to about 24 hours. The reaction can be terminated by quenching the mixture, for example, by addition of water and aqueous NaOH and cooling. Work-up of the reduction reaction mixture and isolation of the reduced product can be accomplished using conventional procedures known in the art.
- The compositions of the invention can be used for the reduction of a variety of organic compounds including without limitation aldehydes, ketones, esters, amides, epoxides, nitrites, and other imides. Exemplary compounds which can be reduced in accordance with the invention include (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (to (+1-) trans 4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine), N-methylsuccinimide, ethyl 1-methylnipecotate, and the like.
- For example, typical reducing agents and yields are listed in the table below for the reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione to (+/−) trans 4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine.
REAGENT YIELD Sodium Aluminum Hydride 45%1 Lithium Aluminum Hydride 65-75%2 Composition of the Invention 85%3 - It is reported in the literature that commercial sodium aluminum hydride (NaAlH4) is capable of reducing selected organic functional groups including aldehydes, ketones, esters, carboxylic acids, epoxides, amides, imides, and sulfoxides. Many times, however, the yields are lower using sodium aluminum hydride instead of lithium aluminum hydride, as demonstrated by the above table. See also Example 4 below, which demonstrates that use of sodium aluminum hydride alone as the reducing agent resulted in reduction product yields from 45 to 55%, using toluene/THF solvent mixtures and THF alone. Use of LiCl in limiting amounts (0.1 equivalent) also gave low yields (50%).
- The inventors have found that the reactivity of sodium aluminum hydride can be improved by the addition of various additives. Thus, in accordance with this invention, reductions can be accomplished with sodium aluminum hydride when its activity is modified with various additives as described above. For example, the additive lithium chloride could be mixed with sodium aluminum hydride in order to produce a resulting hydride composition that performs as well as lithium aluminum hydride alone.
- It is also known that LiCl can be reacted with NaAlH4 in stoichiometric amounts to form lithium aluminum hydride, which is then separated from the by-product, NaCl, prior to use. This metathesis reaction, however, requires the addition of a catalyst, such as a small amount of LiAlH4, to initiate the reaction, or alternatively a NaAlH4 solution forming prestep. In this invention LiCl can be added in less than stoichiometric amounts, and without requiring LiAlH4 as a catalyst, or a NaAlH4 solution forming prestep. As discussed above, when the starting compounds include sodium aluminum hydride and lithium chloride, the order of addition of the additive is important. However, it is not currently believed that the order of addition of the additives is critical when using other starting materials, in which case it is currently believed that the additives can be added at various times during the entire reduction.
- Although reductions performed with LiAlH4 provide better yields than when using NaAlH4 (i.e., NaAlH4 without additives may be less reactive in some cases), LiAlH4 is much more expensive than NaAlH4. Reductions of functional groups, especially imides, employing NaAIH4 in accordance with the invention, however, with the appropriate additives gave identical results as obtained when using the more costly commercial LiAlH4.
- The present invention also describes less expensive alternatives for organic functional group reductions, using in situ generated alkali hydride reducing agents. This aspect of the present invention overcomes prior difficulties associated with the commercial preparation of lithium aluminum hydride. It has been discovered that unfiltered solutions of lithium aluminum hydride (equations 1 to 5) are capable of reduction of functional groups, especially imides. Unfiltered lithium aluminum hydride prepared from sodium aluminum hydride and lithium chloride, or unfiltered lithium or sodium aluminum hydride prepared from the elements can be used directly in subsequent reduction of the substrate. If required for yield improvement, other additives can be added to the sodium aluminum hydride. The resulting unfiltered, in situ-prepared hydride reducing agents are used directly for reduction of a substrate in an organic solvent. Overall this process saves in number of filtration steps, causes filtrations to be safer, and reduces the handling large amounts of ethereal solvents required for the preparation of the reducing agent. The yields with the in situ reduction protocol are essentially identical to the yields obtained when the reduction is performed with filtered lithium aluminum hydride solution. Further, all functional groups that are typically reduced with filtered lithium aluminum hydride are reduced with the unfiltered lithium aluminum hydride solutions. Work-up of the reduction reaction and isolation of the reduced product involves employment of the standard procedure used for commercial lithium aluminum hydride. The inorganic by-products are most often removed by filtration or become part of any aqueous phase that may be present.
- For example, reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione or (+/−) trans 3-methoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione with unfiltered lithium aluminum hydride afforded (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yields and with similar impurity profiles as with commercial LiAlH4.
-
- For example, reduction of (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione with in situ modified NaAIH4 afforded (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and with similar impurity profile as with commercial LiAlH4.
- Optionally, inorganic or organic additives can be added to either reduction protocol to aid the reduction. These additives can be employed in 0.01 equivalents up to and including 5 equivalents. Examples of useful additives, which can be used in combination as well, include, but are not limited to LiCl, HCl, LiBr, AlCl3, TiCl4, AlBr3, TiBr4, LiAlH4, NaBH4, LiBH4, LiBH(R)3, NaBH3 (anilide), THF-BH3, LiAlH(OMe)3, LiAlH(O-t-Bu)3, NaAlH2 (OC2H4OCH3), AlH3; ethers such as methyl t-butyl ether, dimethoxyethane, glymes; alcohols such as methanol, ethanol, isopropanol, t-butanol, ethereal alcohols and/or their corresponding metal alkoxides; primary and/or secondary amines both aromatic and/or aliphatic and their corresponding metal amides; and tertiary amines such as tetramethylethylene diamine, triethylamine.
- A 500 ml., three-necked round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 10.00 grams (0.237 mole) of anhydrous lithium chloride, and 70 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed. This slurry was stirred at room temperature for 30 minutes. A slurry of 12.80 grams (90% assay NaAlH4, 0.213 mole) in 24 ml. of toluene was added. An exotherm of 9° C. was observed within four minutes.
- This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.
- The dark gray slurry was employed in a reduction after stirring at room temperature for one hour.
- A 500 ml., three-necked, jacketed, round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 13.80 grams (0.327 mole) of anhydrous lithium chloride, and 97 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed. This slurry was stirred at room temperature for five hours. The slurry was cooled to 0° C. with a chiller. A slurry of 13.00 grams (95% assay NaAlH4, 0.229 mole) in 38 ml. of toluene was added. An exotherm of 9° C. was observed immediately.
- This slurry was stirred at less than 10° C. for one hour, then allowed to gradually warm to ambient temperature overnight.
- This slurry was prepared from 15.5 mole % lithium chloride, 56.8 mole % tetrahydrofuran, 10.9 mole % sodium aluminum hydride, and 16.9 mole % toluene.
- The dark gray slurry was employed in a reduction after stirring at room temperature overnight.
- A 500 ml., three-necked round-bottom flask was fitted with a mechanical stirrer, a Teflon® stopper, and a Claisen adapter fitted with a dry ice condenser, a Teflon® clad thermocouple, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 10.00 grams (0.237 mole) of anhydrous lithium chloride, and 70 ml. of tetrahydrofuran. The resultant slurry was stirred at 350 RPMs. A slight exotherm, 3° C., was observed. This slurry was stirred at room temperature for 30 minutes. A slurry of 12.80 grams (90% assay NaAlH4, 0.213 mole) in 24 ml. of toluene was added. An exotherm of 9° C. was observed within four minutes.
- This slurry was prepared from 15.3 mole % lithium chloride, 56.1 mole % tetrahydrofuran, 13.9 mole % sodium aluminum hydride, and 14.7 mole % toluene.
- The dark gray slurry was employed in a reduction after stirring at 70° C. for two hours.
- A 500 ml., three-necked, jacketed flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with tetrahydrofuran, 70 ml. This solution was stirred at 350 RPMs and cooled to 0° C. with a circulating chiller. Sodium aluminum hydride, 12.11 grams of 95% assay (2.70 equivalents, 213 mmole) was added to the reactor. An immediate exotherm of 8° C. was noted, which quickly subsided. Toluene, 24 ml., was then added. This suspension was stirred at 0° C. for an additional thirty minutes. A dry, 250 ml., single-necked flask was fitted with a large, egg-shaped magnetic stir bar, and an argon inlet. This flask was purged with argon, then charged with 24.4 grams of 94.5% assay (+/−) trans 3-ethoxy or 3-methoxy carbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1.00 equivalent, 79 mmole) and 65 ml. of toluene. This suspension was stirred at room temperature. After all the imide-ester dissolved, the solution was transferred to the addition funnel. The 250 ml. flask was rinsed with additional toluene, 8 ml, and this was added to the addition funnel. The imide-ester solution was added dropwise. This resulted in a very exothermic reaction. The feed rate was adjusted to maintain the reaction temperature at 10-15° C. Total imide-ester feed time was 62 minutes. After the end of the feed, the reaction mixture was heated to 65° C. for two hours, then recooled to 0° C. Additional toluene, 85 ml., was added. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 9 ml., was then added dropwise. At the end of this feed, the reaction mixture was warmed to 65° C. The reaction mixture was stirred at 65° C. for thirty minutes, recooled to 27° C., then the solids were collected on a Büchner funnel. The solids were reslurried with toluene (2×30 ml.). The filtrate was two layers. It was concentrated on the rotary evaporator to 250 ml., and transferred to a separatory funnel. The mixture was diluted with water (100 ml.) and toluene (100 ml.). The aqueous layer was drawn off and discarded. The organic layer was washed with water (1×100 ml.), and dried with magnesium sulfate. The desired product was isolated by precipitation from the organic layer, washed, air dried, then dried in a vacuum desiccator overnight.
- This afforded a white solid, yield=8.01 grams, 45.4%.
- A 500 ml., four-necked, round bottom flask was equipped with a mechanical stirrer, a 125 ml. pressure-equalizing addition funnel, a Teflon® stopper and a Claisen adapter fitted with a Teflon® clad thermocouple, a dry ice condenser, and an argon inlet. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. Lithium chloride, 9.85 grams (2.64 equivalents, 232.36 mmole) was added. The flask was then charged with tetrahydroflran, 67 ml. This solution was stirred at 350 RPMs. Sodium aluminum hydride, 12.01 grams of 95% assay (2.40 equivalents, 211.24 mmole) slurried in toluene, 21 ml., was added to the reactor. The slurry composition was prepared from 15.8 mole % lithium chloride, 56.3 mole % tetrahydrofuran, 14.4 mole % sodium aluminum hydride, and 13.4 mole % toluene. Additional tetrahydrofuran, 39 ml., was added and this suspension was stirred at room temperature for fifty minutes. Toluene, 31 ml., was then added. This suspension was cooled to 10° C. and stirred for an additional five minutes. A dry, 250 ml., single-necked flask was fitted with a large, egg-shaped magnetic stir bar, and an argon inlet. This flask was purged with argon, then charged with 27.1 grams of 94.5% assay (+/−) trans 3-ethoxy or 3-methoxy carbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1.00 equivalent, 88 mmole) and 69 ml. of toluene. This suspension was stirred at room temperature. After all of the imide ester had dissolved, the solution was transferred to the addition funnel. The imide-ester solution was added dropwise. This resulted in a very exothermic reaction. The feed rate was adjusted to maintain the reaction temperature at 10-15° C. After the end of the feed, the 250 ml. flask was rinsed with additional toluene, 7 ml, and this was added to the addition funnel. The reaction mixture was heated to 75° C. for three hours, then recooled to 10° C. Additional toluene, 50 ml., was added. The speed of the agitator was increased to 500 RPMs. This was followed by slow addition of 9 ml. of water. The reaction mixture got very thick at the end of this addition. Aqueous sodium hydroxide, 15%, 9 ml., was then added dropwise. The solid started to break up at the end of this addition. Water, 18 ml., was then added dropwise. At the end of this feed, the reaction mixture was warmed to 65° C. for twenty minutes and the stirrer was slowed to 350 RPMs. The reaction mixture was then cooled to 400° C., then the solids were collected on a Buchner funnel. The solids were reslurried with toluene (2×31 ml.). The desired product was isolated by precipitation from the combined filtrates, washed, air dried, then dried in a vacuum desiccator overnight.
- This afforded a white solid, yield=16.85 grams, 85.9%.
-
- To a cooled solution of lithium chloride (0.11 mol) in THF is added NaAlH4 (0.22 mol) in toluene/THF under argon. N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The insoluble inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain a solution which contained N-methyl pyrrole, as determined by GLC analysis. Similar results were obtain using 0.02 mole of lithium chloride, but a longer heating period is required.
-
- To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon is added lithium tert-butoxide (0.11 mol) in THF. N-methylsuccinimide (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (5 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain solution which contained N-methyl pyrrole, as determined by GLC analysis.
-
- To a cooled solution of filtered or unfiltered LiAlH4 (2 mole) under argon was added N-methylsuccinimide (1 mole) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H2O, and aqueous NaOH using appropriate cooling. The solution was filtered and solids were washed with fresh THF. The yields were determined by GC analysis of crude filtered reaction solutions using nonane as an internal standard. Essentially no difference in yields was observed with filtered or unfiltered LiAlH4 solutions.
-
- To a cooled solution of filtered or unfiltered LiAlH4 (2 mole) under argon was added ethyl 1-methylnipecotate (1 mole) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H2O, and aqueous NaOH using cooling as required. The solution was then filtered and solids were washed with fresh THF. Yields were determined by GC analysis of crude filtered reaction solutions using nonane as an internal standard. Essentially no difference in yields was observed with filtered or unfiltered LiAlH4 solutions.
-
- To a cooled solution of filtered or unfiltered LiAlH4 (2.7 mol) in THF under argon as added (+/−) trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (1 mol) in THF. After addition was complete, reaction was heated to 40 to 50° C. for 2 hr and then stirred overnight at room temperature. The reaction was quenched by adding H2O, and aqueous NaOH using cooling as required. The solution was then filtered and solids were washed with fresh THF. The filtrate was analyzed by NMR and HPLC. The presence of unreduced product was not detectable by 1H NMR for either filtered or unfiltered LiAlH4.
- To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, reaction was allowed to warm to room temperature. After 30 minutes at room temperature, the reaction was heated to >40° C. for 2 hr. The reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH were used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in lower yield (but similar impurity profile as with LiAlH4) as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
- To a cooled solution of LiAlH4 (0.22 mol) in toluene/THF under argon was added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition was complete, the reaction was allowed to warm to room temperature. After 30 minutes at room temperature reaction was heated to >40° C. for 2 hr. Reaction was then cooled to <5° C. and toluene (50 ml) was added. Water (9 ml) was then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH was used as necessary. The solid inorganic salts were removed by filtration. These solids were washed with additional THF or toluene. The filtered solution was then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in higher yield (but similar impurity profile) as with NaAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvent.
- To a cooled 50:50 mole mixture of NaAlH4/LiAlH4 (0.22 mol) in toluene/THF under argon is added (+/−) trans-3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) in THF holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. Reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
- To a cooled mixture of NaAlH4 (0.22 mol) in toluene is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH4 or after the addition of the substrate, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione. Next, (+/−)trans 3-ethoxycarbonyl-4-(4′-fluorophenyl)-N-methyl-piperidine-2,6-dione (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene. The filtered solution is then concentrated to give (+/−) trans-4-(4′-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine in essentially the same yield and similar impurity profile as with LiAlH4 as shown by HPLC analysis. The product can be recovered by standard procedures such as trituration with a less polar solvents.
-
- To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon is added LiCl (0.11 mol) in THF. Note: LiCl can be added to the reactor prior to the addition of NaAlH4 or after the addition of the substrate. N-methylsuccinimide (0.083 mol) in THF is added holding the temperature below 15° C. After addition is completed, reaction is allowed to warm to room temperature. After 30 minutes at room temperature reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (50 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The insoluble inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain a solution which contained N-methyl pyrrole, as determined by GLC analysis. Similar results were obtained using 0.02 mole of lithium chloride, but a longer heating period is required.
-
- To a cooled solution of NaAlH4 (0.22 mol) in toluene/THF under argon is added lithium tert-butoxide (0.11 mol) in THF. N-methylsuccinimide (0.083 mol) is added in THF (65 ml) holding the temperature below 15° C. After addition is complete, the reaction is allowed to warm to room temperature. After 30 minutes at room temperature, the reaction is heated to >40° C. for 2 hr. The reaction is then cooled to <5° C. and toluene (5 ml) is added. Water (9 ml) is then added slowly holding the temperature below 15° C. Additional H2O or aqueous NaOH is used as necessary. The solid inorganic salts are removed by filtration. These solids are washed with additional THF or toluene to obtain solution which contained N-methyl pyrrole, as determined by GLC analysis.
- It is understood that upon reading the above description of the present invention, one skilled in the art could make changes and variations therefrom. These changes and variations are included in the spirit and scope of the following appended claims.
Claims (27)
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WO2007026018A1 (en) * | 2005-09-01 | 2007-03-08 | Chemetall Gmbh | Solutions of lithium aluminium hydride |
WO2015071831A1 (en) * | 2013-11-18 | 2015-05-21 | Piramal Enterprises Limited | An improved process for minimising the formation of dehalogenated byproducts |
CN104892491A (en) * | 2015-05-06 | 2015-09-09 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
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DE10237441A1 (en) * | 2002-08-16 | 2004-02-26 | Chemetall Gmbh | Direct preparation of lithium aluminum hydride solution from synthesis solution in diethyl ether involves solvent exchange with solvent having greater complexing energy and distillation |
WO2007092602A2 (en) * | 2006-02-08 | 2007-08-16 | Los Alamos National Security, Llc | Composition and method for storing and releasing hydrogen |
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WO1997006097A1 (en) | 1995-08-09 | 1997-02-20 | Fmc Corporation | Process for the preparation of lithium aliminum hydride in ethereal solvents |
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WO2007026018A1 (en) * | 2005-09-01 | 2007-03-08 | Chemetall Gmbh | Solutions of lithium aluminium hydride |
US8840805B2 (en) | 2005-09-01 | 2014-09-23 | Chemetall Gmbh | Solutions of lithium aluminum hydride |
CN101300192B (en) * | 2005-09-01 | 2014-10-15 | 凯密特尔有限责任公司 | Solutions of lithium aluminium hydride |
WO2015071831A1 (en) * | 2013-11-18 | 2015-05-21 | Piramal Enterprises Limited | An improved process for minimising the formation of dehalogenated byproducts |
CN104892491A (en) * | 2015-05-06 | 2015-09-09 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
CN104892491B (en) * | 2015-05-06 | 2017-05-17 | 浙江海森药业有限公司 | Method for synthesizing paroxetine chiral intermediate |
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