US20220204534A1 - Apparatus and continuous flow process for production of boronic acid derivative - Google Patents
Apparatus and continuous flow process for production of boronic acid derivative Download PDFInfo
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- US20220204534A1 US20220204534A1 US17/698,719 US202217698719A US2022204534A1 US 20220204534 A1 US20220204534 A1 US 20220204534A1 US 202217698719 A US202217698719 A US 202217698719A US 2022204534 A1 US2022204534 A1 US 2022204534A1
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- United States
- Prior art keywords
- continuous flow
- vessel
- compound
- flow conduit
- optionally substituted
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 26
- 150000001642 boronic acid derivatives Chemical class 0.000 title abstract description 8
- 238000005112 continuous flow technique Methods 0.000 title description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 236
- 150000001875 compounds Chemical class 0.000 claims description 226
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 134
- -1 substituted Chemical class 0.000 claims description 92
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 78
- 125000000623 heterocyclic group Chemical group 0.000 claims description 52
- 238000001816 cooling Methods 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 47
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 37
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 19
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 229910001220 stainless steel Inorganic materials 0.000 claims description 7
- 239000010935 stainless steel Substances 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- 238000010926 purge Methods 0.000 claims description 6
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
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- 125000004104 aryloxy group Chemical group 0.000 claims description 5
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- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 5
- MZAGXDHQGXUDDX-JSRXJHBZSA-N (e,2z)-4-ethyl-2-hydroxyimino-5-nitrohex-3-enamide Chemical compound [O-][N+](=O)C(C)C(/CC)=C/C(=N/O)/C(N)=O MZAGXDHQGXUDDX-JSRXJHBZSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 3
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 3
- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 134
- 230000008569 process Effects 0.000 abstract description 107
- 238000010924 continuous production Methods 0.000 abstract description 10
- 238000006243 chemical reaction Methods 0.000 description 85
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 70
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- 239000007806 chemical reaction intermediate Substances 0.000 description 45
- 229940126062 Compound A Drugs 0.000 description 42
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 42
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 40
- 125000004432 carbon atom Chemical group C* 0.000 description 39
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- 239000011550 stock solution Substances 0.000 description 31
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- 125000002947 alkylene group Chemical group 0.000 description 27
- 125000003118 aryl group Chemical group 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- CYSWUSAYJNCAKA-FYJFLYSWSA-N ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O Chemical compound ClC1=C(C=CC=2N=C(SC=21)OCC)OC1=CC=C(C=N1)/C=C/[C@H](C)NC(C)=O CYSWUSAYJNCAKA-FYJFLYSWSA-N 0.000 description 22
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 22
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 22
- 239000012535 impurity Substances 0.000 description 21
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 20
- 125000000217 alkyl group Chemical group 0.000 description 20
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 20
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 19
- 125000004122 cyclic group Chemical group 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 14
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 14
- 0 [1*]OC(=O)C[C@H](CC[C@H](NCOCC)B1O[C@@]2(C)[C@H]3C[C@@H](C[C@@]2([H])O1)C3(C)C)O[2*].[1*]OC(=O)c1c([3*])c([3*])c([3*])c(C[C@H](NC(=O)CC)B2O[C@@]3(C)[C@H]4C[C@@H](C[C@@]3([H])O2)C4(C)C)c1O[2*] Chemical compound [1*]OC(=O)C[C@H](CC[C@H](NCOCC)B1O[C@@]2(C)[C@H]3C[C@@H](C[C@@]2([H])O1)C3(C)C)O[2*].[1*]OC(=O)c1c([3*])c([3*])c([3*])c(C[C@H](NC(=O)CC)B2O[C@@]3(C)[C@H]4C[C@@H](C[C@@]3([H])O2)C4(C)C)c1O[2*] 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- XYGKGASSKJWLTN-UHFFFAOYSA-N CCCCCCC.CCCCCCC Chemical compound CCCCCCC.CCCCCCC XYGKGASSKJWLTN-UHFFFAOYSA-N 0.000 description 13
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- 238000004458 analytical method Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 125000005843 halogen group Chemical group 0.000 description 12
- 125000004404 heteroalkyl group Chemical group 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 229910052799 carbon Inorganic materials 0.000 description 11
- 125000005842 heteroatom Chemical group 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 description 8
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- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
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- 239000002253 acid Chemical class 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- SMJRBWINMFUUDS-UHFFFAOYSA-N 2-thienylacetic acid Chemical compound OC(=O)CC1=CC=CS1 SMJRBWINMFUUDS-UHFFFAOYSA-N 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
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- 125000003545 alkoxy group Chemical group 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
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- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
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- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
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- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- SNVLJLYUUXKWOJ-UHFFFAOYSA-N methylidenecarbene Chemical group C=[C] SNVLJLYUUXKWOJ-UHFFFAOYSA-N 0.000 description 1
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001326 naphthylalkyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003551 oxepanyl group Chemical group 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000004929 pyrrolidonyl group Chemical group N1(C(CCC1)=O)* 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000001583 thiepanyl group Chemical group 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/027—Organoboranes and organoborohydrides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/0006—Controlling or regulating processes
- B01J19/0013—Controlling the temperature of the process
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/02—Apparatus characterised by being constructed of material selected for its chemically-resistant properties
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J19/24—Stationary reactors without moving elements inside
- B01J19/248—Reactors comprising multiple separated flow channels
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00002—Chemical plants
- B01J2219/00027—Process aspects
- B01J2219/00033—Continuous processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00049—Controlling or regulating processes
- B01J2219/00051—Controlling the temperature
- B01J2219/00074—Controlling the temperature by indirect heating or cooling employing heat exchange fluids
- B01J2219/00087—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor
- B01J2219/00099—Controlling the temperature by indirect heating or cooling employing heat exchange fluids with heat exchange elements outside the reactor the reactor being immersed in the heat exchange medium
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/02—Apparatus characterised by their chemically-resistant properties
- B01J2219/025—Apparatus characterised by their chemically-resistant properties characterised by the construction materials of the reactor vessel proper
- B01J2219/0277—Metal based
- B01J2219/0286—Steel
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present disclosure relates to a continuous flow process for production of boronic acid derivatives and apparatus of performing the same. More particularly, it relates to a continuous flow process for a large scale production of boronic acid derivatives.
- Boronic acid derivatives are useful as potentiators of antimicrobial compounds.
- Some methods for ⁇ -acylamidoboronic ester synthesis include the addition of the lithium salt of an amine and rearrangement followed by an amide coupling reaction. However, maintenance of low temperature, exclusion of water and careful control of stoichiometry of the reagents are required for good results. These features render the reaction difficult to perform successfully on a production scale, and limit the availability of pharmaceutically important boronic ester and acid compounds. Thus, there remains a need for a process for the easy scale-up production of ⁇ -acylamidoboronic acid derivatives.
- Some embodiments relate to a process for production of a compound of Formula (Ia) or (Ib) or salt thereof,
- Some embodiments relate to an apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof,
- FIG. 1 illustrates a non-limiting schematic of a continuous flow apparatus.
- FIG. 2 illustrates a non-limiting schematic of a continuous flow apparatus.
- the disclosed technology relates to a continuous flow process for the production of boronic acid derivatives.
- the process allows a continuous production of boronic acid derivatives with a high yield and simplified steps.
- the process specifically provides for the production of a key reaction intermediate in a process to prepare useful boronic acid derivatives.
- the reaction intermediate has the structure of Compound A:
- the batch process for the synthesis of Compound A involves a LHMDS mediated addition/arrangement reaction of compound 2a, followed by an EDCl/HOBt mediated amide coupling reaction of compound 2d with an ester (e.g., a thienylacetic acid compound 2e) as shown in Scheme 1.
- an ester e.g., a thienylacetic acid compound 2e
- the continuous process described herein allows for continuous synthesis of a first reaction intermediate (e.g., compound 2b) and a second reaction intermediate (e.g., compound 2d), with a high or full conversion of the starting reagent, the compound of formula (IIa) or (IIb) (e.g. compound 2a). Because of the full conversion of the starting reagent (e.g., compound 2b) and a second reaction intermediate (e.g., compound 2d), with a high or full conversion of the starting reagent, the compound of formula (IIa) or (IIb) (e.g. compound 2a). Because of the full conversion of the starting reagent (e.g.
- the continuous flow containing the second reaction intermediate e.g., compound 2d
- the continuous flow containing the second reaction intermediate can be added directly into a vessel that has a compound of formula III (e.g., compound 2e) or the reagents used to make a compound of formula III (e.g., HOBt/EDCl mediated amidation with a 2-thienylacetic acid for making compound 2e). Therefore, the process described herein allows for synthesis of compound A from the starting material compound of formula (IIa) or (IIb) without the need to separate or purify the reaction intermediate or the compound of formula III (e.g., the reaction intermediate compound 2d and/or the compound of formula III).
- This process and apparatus for conducting this process simplifies the synthesis steps and leads to an increased productivity. They also lead to better scalability, energy efficiency, shorter production time, and fewer reaction vessels required.
- Some embodiments include production of the second reaction intermediate (e.g., compound 2d) and the compound of formula (III) (e.g., compound 2e) in parallel, which can then be reacted together to produce a compound of formula (Ia) or (Ib) (e.g. Compound A) without the need to purify each compound prior to reaction.
- the process described herein leads to better scalability and energy efficiency as well as saving reaction time and reaction vessels.
- the process operates under cryogenic conditions; however, reaction temperatures below ⁇ 70° C. used for batch production can be avoided. In some embodiments, temperatures of ⁇ 30° C. can be used to provide a more readily scalable process with better reproducibility and higher yield.
- the compound of formula (IIa) or (IIb) e.g., compound 2a
- the reaction flow carrying the second reaction intermediate e.g., compound 2d
- the reaction vessel in which the compound of formula (III) is made without the need to purify the second reaction intermediate or the compound of formula (III) prior to reaction of the two together.
- the chiral boronic ester compound A is an intermediate in the synthesis of Compound B, a ⁇ -lactamase inhibitor.
- a continuous process In a continuous process, separate continuous flow conduits are used for each step of the reaction, and the reaction mixture flows from one operation to the next within the production line.
- the operations are performed continuously and some of the reaction parameters such as flow rate, molar ratio, and reaction temperatures can be easily and quickly adjusted based on a concurrent monitoring of the reaction product. Consequently, a continuous production process requires much smaller equipment volumes for achieving the same production capacity.
- a continuous operation helps to ensure the quality of the product.
- a continuous flow process may be preferable over a traditional batch process as it would mitigate the risks that are associated with potentially hazardous decomposition or other side reactions of the lithium amide.
- the shorter residence times in continuous flow set-up can allow operation at higher temperatures.
- the continuous process described herein achieves full or near full conversion of the second reaction intermediate, which makes it possible to add the continuous flow containing the second reaction intermediate directly to the vessel containing the compound of Formula (III) without any purification or separation of the second reaction intermediate.
- a continuous flow process and the apparatus for performing the continuous flow process are often complicated to design and highly specific to the types of reaction product and production rate.
- the continuous flow process described herein by utilizing a continuous flow process to produce a reaction intermediate and performing the last amidation step in a non-continuous-flow vessel, has shown great reproducibility and high yield as compared to the other types continuous flow processes that involve performing the last quenching step inside a continuous flow conduit. Additionally, the continuous flow process described herein has allowed successful production of the compound of formula I, particularly compound A in a large scale with a high yield.
- substantially free of water means a product has been dried using standard techniques known in the art. In some embodiments, “substantially free of water” means the product contains less than 0.5%, 1%, 3%, or 5% of water. In some embodiments, “substantially free of water” means the product contains less than 0.1% of water or no water.
- continuous flow conduit refers to any pipe, tube, channel, channeled plate, or any other vessel of suitable shape for conveying fluids in a continuous flow process.
- reaction time refers to the time required for the reaction mixture or stock solution to flow from the input to the output of a continuous flow conduit.
- thermally coupled refers to a direct or indirect coupling between two objects in way that facilitates heat transfer between the two objects.
- the vessel or continuous flow conduit can be immersed in the cooling bath to achieve a desired temperature.
- fluidly coupled means that a first component are in fluid communication with another component. Such fluid communication may be achieved by either direct or indirect connection via valves, pipes, conveyors, pumps, conduits and any other suitable connectors known by those skilled in the art.
- Ca to Cb or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms.
- a “C 1 to C 4 alkyl” or “C 1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 —, CH 3 CH 2 —, CH 3 CH 2 CH 2 —, (CH 3 ) 2 CH—CH 3 CH 2 CH 2 CH 2 —, CH 3 CH 2 CH(CH 3 )— and (CH 3 ) 3 C—.
- halogen or “halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
- alkyl refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds).
- the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms.
- the alkyl group could also be a lower alkyl having 1 to 4 carbon atoms.
- the alkyl group of the compounds may be designated as “C 1-4 alkyl” or similar designations.
- C 1-4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
- alkoxy refers to the formula —OR wherein R is an alkyl as is defined above, such as “C 1-9 alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
- alkylthio refers to the formula —SR wherein R is an alkyl as is defined above, such as “C 1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.
- alkenyl refers to a straight or branched hydrocarbon chain containing one or more double bonds.
- the alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
- the alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms.
- the alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms.
- the alkenyl group of the compounds may be designated as “C 2-4 alkenyl” or similar designations.
- C 2-4 alkenyl indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl.
- Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
- alkynyl refers to a straight or branched hydrocarbon chain containing one or more triple bonds.
- the alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
- the alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms.
- the alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms.
- the alkynyl group of the compounds may be designated as “C 2-4 alkynyl” or similar designations.
- C 2-4 alkynyl indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl.
- Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
- heteroalkyl refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone.
- the heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated.
- the heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms.
- the heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms.
- the heteroalkyl group of the compounds may be designated as “C 1-4 heteroalkyl” or similar designations.
- the heteroalkyl group may contain one or more heteroatoms.
- C 1-4 heteroalkyl indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
- aromatic refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine).
- carbocyclic aromatic e.g., phenyl
- heterocyclic aromatic groups e.g., pyridine
- the term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
- aryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic.
- the aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms.
- the aryl group may be designated as “C 6-10 aryl,” “C 6 or C 10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
- aryloxy and arylthio refers to RO— and RS—, in which R is an aryl as is defined above, such as “C 6-10 aryloxy” or “C 6-10 arylthio” and the like, including but not limited to phenyloxy.
- an “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such “C 7-14 aralkyl” and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl.
- the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
- heteroaryl refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone.
- heteroaryl is a ring system, every ring in the system is aromatic.
- the heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated.
- the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members.
- the heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations.
- heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
- heteroarylkyl or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl.
- the alkylene group is a lower alkylene group (i.e., a C 1-4 alkylene group).
- carbocyclyl means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls.
- the carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated.
- the carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms.
- the carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms.
- the carbocyclyl group may be designated as “C 3-6 carbocyclyl” or similar designations.
- carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
- a “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C 4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
- the alkylene group is a lower alkylene group.
- cycloalkyl means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- cycloalkenyl means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic.
- An example is cyclohexenyl.
- heterocyclyl means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system.
- the heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated.
- the heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members.
- the heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members.
- the heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations.
- the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S.
- heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydr
- a “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
- acyl refers to —C( ⁇ O)R, wherein R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- R is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
- O-carboxy refers to a “—OC( ⁇ O)R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- C-carboxy refers to a “—C( ⁇ O)OR” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- a non-limiting example includes carboxyl (i.e., —C( ⁇ O)OH).
- a “cyano” group refers to a “—CN” group.
- a “cyanato” group refers to an “—OCN” group.
- An “isocyanato” group refers to a “—NCO” group.
- a “thiocyanato” group refers to a “—SCN” group.
- An “isothiocyanato” group refers to an “—NCS” group.
- a “sulfinyl” group refers to an “—S( ⁇ O)R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- a “sulfonyl” group refers to an “—SO 2 R” group in which R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- S-sulfonamido refers to a “—SO 2 NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- N-sulfonamido refers to a “—N(R A )SO 2 R B ” group in which R A and R b are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “O-carbamyl” group refers to a “—OC( ⁇ O)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- N-carbamyl refers to an “—N(R A )OC( ⁇ O)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “O-thiocarbamyl” group refers to a “—OC( ⁇ S)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, a C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- N-thiocarbamyl refers to an “—N(R A )OC( ⁇ S)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- a “C-amido” group refers to a “—C( ⁇ O)NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- N-amido refers to a “—N(R A )C( ⁇ O)R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- amino group refers to a “—NR A R B ” group in which R A and R B are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- aminoalkyl refers to an amino group connected via an alkylene group.
- alkoxyalkyl refers to an alkoxy group connected via an alkylene group, such as a “C 2-8 alkoxyalkyl” and the like.
- a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group.
- substituted it is meant that the group is substituted with one or more substitutents independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy), C 3 -C 7 -carbocyclyl-C 1 -C 6 -alkyl (optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C
- substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C 1 -C 4 alkyl, amino, hydroxy, and halogen.
- radical naming conventions can include either a mono-radical or a di-radical, depending on the context.
- a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical.
- a substituent identified as alkyl that requires two points of attachment includes di-radicals such as —CH 2 —, —CH 2 CH 2 —, —CH 2 CH(CH 3 )CH 2 —, and the like.
- Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”
- alkylene means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl).
- the alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated.
- the alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms.
- the alkylene group could also be a lower alkylene having 1 to 4 carbon atoms.
- the alkylene group may be designated as “C 1-4 alkylene” or similar designations.
- C 1-4 alkylene indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.
- alkenylene means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment.
- the alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated.
- the alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms.
- the alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms.
- the alkenylene group may be designated as “C 2-4 alkenylene” or similar designations.
- C 2-4 alkenylene indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl
- the compounds described herein including but not limited to the compounds of formula (Ia), (Ib), (IIa), (IIb), (III), (IVa), (IVb), (Va), (Vb), (VI), the first reaction intermediate, or the second reaction intermediate, should be understood to also include the ionic form of the compound when in solution.
- Salts described herein include but are not limited to salts of such compound with an organic or inorganic acid or with an organic or inorganic base.
- the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
- Acid addition salts can be formed with inorganic acids and organic acids.
- Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
- Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
- Base addition salts can be formed with inorganic and organic bases.
- Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts.
- Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated by reference herein in its entirety).
- One aspect of the present technology relates to a process for production of a compound of Formula (Ia) or (Ib) or salt thereof,
- transitioning the first reaction intermediate to a second temperature to yield a second reaction intermediate comprises delivering the first reaction intermediate to a second continuous flow conduit at the second temperature to yield the second reaction intermediate.
- the second reaction intermediate is collected in a vessel wherein the vessel does not have a continuous outflow. In some embodiments, the second reaction intermediate is collected in a vessel wherein the vessel is a continuous outflow or includes at least one continuous flow.
- the lithium amide solution can be a continuous flow of the lithium amide in one or more suitable organic solvents.
- the first continuous flow of the lithium amide is a continuous flow of the lithium amide in tetrahydrofuran, heptane, hexane, cyclohexane, toluene, or any combinations thereof.
- the first continuous flow of the lithium amide is a continuous flow of the lithium amide in tetrahydrofuran.
- the providing a first continuous flow of a lithium amide further comprises
- the second continuous flow of the lithium amide can be in one or more suitable solvents.
- the second continuous flow of the lithium amide is in tetrahydrofuran.
- a lithium amide can be a dipolar compound represented by the general formula RR′NLi or LiN(SiR 3 )(SiR′ 3 ), wherein R and R′ are each independently selected from, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 3-7 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C 1-6 alkylene-C 3-7 carbocyclyl, optionally substituted C 1-6 alkylene-5-10 membered heterocyclyl, optionally substituted C 1-6 alkylene-C 6-10 aryl, or optionally substituted C 1-6 alkylene-5-10 membered heteroaryl.
- R and R′ are each independently selected from, optionally substituted C 1-10 alkyl, optionally substituted C 2-10 alkenyl, optionally
- the lithium amide is lithium bis(trimethylsilyl)amide. In some embodiments, the lithium amide is lithium diisopropylamide, lithium diethylamide, lithium pyrrolidide, lithium piperidide, or lithium 2,2,6,6,-tetramethylpiperidide.
- the continuous flow of the compound of Formula (IIa) or (IIb) can be a continuous flow of the compound of Formula (IIa) or (IIb) in one or more suitable organic solvents.
- the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in tetrahydrofuran.
- the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in heptane.
- the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in heptane and tetrahydrofuran.
- a solution of the compound of Formula (IIa) or (IIb) stored in a vessel may be combined with additional organic solvent (e.g., tetrahydrofuran) to reach a more preferred concentration before the solution flows out of the vessel.
- a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 20% to 60% by weight of the compound of Formula (IIa) or (IIb).
- a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 25% to 55% by weight of the compound of Formula (IIa) or (IIb).
- a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 25% to 35% by weight of the compound of Formula (IIa) or (IIb).
- the vessel storing a solution of the compound of Formula (IIa) or (IIb) can be pressurized to generate a preferred flow rate for the compound of Formula (IIa) or (IIb).
- the flow rate of the compound of Formula (IIa) or (IIb) is in the range of about 0.17 kg/h to about 0.23 kg/h. In some embodiments, the flow rate is in the range of about 0.1 kg/h to about 0.4 kg/h. In some embodiments, the flow rate is in the range of about 0.15 kg/h to about 0.25 kg/h. In some embodiments, the flow rate is about 0.19 kg/h.
- the first reaction intermediate comprises a compound having the structure of formula (IVa) or (IVb) or salt thereof
- the first reaction intermediate comprises a compound having the structure of formula (IVa). In some embodiments, the first reaction intermediate comprises
- the second reaction intermediate comprises a compound having the structure of formula (Va) or (Vb) or salt thereof
- the second reaction intermediate comprises a compound having the structure of formula (Va). In some embodiments, the second reaction intermediate comprises
- the process described herein can further include preparing the reagents or solvents used in the process under an inert atmosphere.
- the process described herein can further include preparing the lithium amide, the compound of formula (IIa) or (IIb), and the tetrahydrofuran under a nitrogen or argon atmosphere.
- the process can include preparing the compound of formula (III) under an inert atmosphere.
- the reagents and solvents used in this process can be substantially free of water.
- the lithium amide, the compound of formula (IIa) or (IIb), the trimethylsilyl chloride, and the tetrahydrofuran used in the process are substantially free of water.
- the process described herein can further include combining trimethylsilyl chloride to the compound of formula (IIa) or (IIb) prior to providing a continuous flow of a compound of formula (IIa) or (IIb).
- the continuous flow of the compound of formula (IIa) or (IIb) include trimethylsilyl chloride.
- the continuous flow of the compound of formula (IIa) or (IIb) does not include trimethylsilyl chloride.
- the process described herein can further include preparing a compound of formula (III) in a vessel downstream of the second continuous flow conduit.
- preparing the compound of formula (III) includes combining a compound of formula (VI) G-(CH 2 ) n —COOH (VI), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl), and Hydroxybenzotriazole (HOBt) in a vessel.
- preparing the compound of formula (III) is performed at a temperature in the range of about ⁇ 10° C. to 10° C.
- preparing the compound of formula (III) is performed at 0° C.
- the process can further include pre-cooling the lithium amide to a temperature in the range of about ⁇ 50° C. to about 0° C.
- the pre-cooling process can include one or more stages of gradually lowering the temperature.
- the pre-cooling described herein can include a first stage of lowering the temperature and a second stage of further lowering the temperature.
- the process described herein can include pre-cooling the lithium amide to a temperature of about ⁇ 90° C., ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 65° C., ⁇ 60° C., ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 25° C., ⁇ 10° C., or ⁇ 5° C. prior to delivering the lithium amide to the first continuous flow conduit.
- the process described herein can further include a first stage of pre-cooling the lithium amide to a temperature in the range of about ⁇ 100° C. to 0° C., ⁇ 90° C.
- the process described herein can further include a first stage of pre-cooling the lithium amide to a temperature in the range of about ⁇ 30° C. to 0° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran.
- the process described herein can further comprise pre-cooling the tetrahydrofuran.
- the tetrahydrofuran can be pre-cooled to a temperature in the range of about ⁇ 80° C. to ⁇ 20° C. prior to being combined with the separate continuous flow of the lithium amide.
- the tetrahydrofuran can be pre-cooled to a temperature in the range of about ⁇ 80° C. to ⁇ 65° C. prior to being combined with the separate continuous flow of the lithium amide.
- the tetrahydrofuran can be pre-cooled to a temperature of about ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 65° C., or ⁇ 60° C. prior to the being combined with the continuous flow of tetrahydrofuran and the second continuous flow of the lithium amide.
- the tetrahydrofuran can be pre-cooled to a temperature of in the range of about ⁇ 100° C. to ⁇ 0° C., ⁇ 90° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 20° C., ⁇ 70° C.
- the process described herein can further comprise pre-cooling the separate continuous flow of the lithium amide.
- the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about ⁇ 80° C. to ⁇ 10° C. prior to being combined with the continuous flow of tetrahydrofuran.
- the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about ⁇ 80° C. to ⁇ 10° C. prior to being combined with the continuous flow of tetrahydrofuran.
- the separate continuous flow of the lithium amide can be pre-cooled to a temperature of about ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 60° C., 60° C., ⁇ 55° C., ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., or ⁇ 5° C. prior to being combined with the continuous flow of tetrahydrofuran.
- the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about ⁇ 100° C. to ⁇ 0° C., ⁇ 90° C. to ⁇ 10° C., ⁇ 80° C.
- the process can further include pre-cooling the tetrahydrofuran to a temperature in the range of about ⁇ 100° C. to about 0° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran.
- the process described herein can further include pre-cooling the tetrahydrofuran to a temperature of about ⁇ 90° C., ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 65° C., ⁇ 60° C., ⁇ 55° C., ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., or ⁇ 5° C.
- the process described herein can further include pre-cooling the tetrahydrofuran to a temperature in the range of about ⁇ 100° C. to ⁇ 0° C., ⁇ 90° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 20° C., ⁇ 70° C. to ⁇ 20° C., ⁇ 70° C. to ⁇ 10° C., ⁇ 60° C. to ⁇ 20° C., ⁇ 60° C. to ⁇ 10° C., ⁇ 50° C.
- the process described herein can further include pre-cooling the tetrahydrofuran to about ⁇ 30° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran.
- the process can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature suitable for the lithium amide addition reaction.
- the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about ⁇ 100° C. to about 0° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb).
- the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature of about ⁇ 90° C., ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 65° C., ⁇ 60° C., ⁇ 55° C., ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., or ⁇ 5° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb).
- the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature of about ⁇ 30° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb). In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about ⁇ 50° C. to 0° C. or ⁇ 30° C. to 0° C. prior to the combining of the continuous flow of the first reaction intermediate and the continuous flow of the compound of Formula (IIa) or (IIb).
- the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about ⁇ 100° C. to 0° C., ⁇ 90° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 10° C., ⁇ 80° C. to ⁇ 20° C., ⁇ 70° C. to ⁇ 20° C., ⁇ 70° C. to ⁇ 10° C., ⁇ 60° C. to ⁇ 20° C., ⁇ 60° C. to ⁇ 10° C., ⁇ 50° C. to ⁇ 20° C., ⁇ 50° C. to ⁇ 10° C., ⁇ 40° C.
- the process described herein can further include maintaining the first continuous flow conduit at a temperature in the range of about ⁇ 100° C. to about 0° C. during the process. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about ⁇ 85° C., ⁇ 80° C., ⁇ 75° C., ⁇ 70° C., ⁇ 65° C., 60° C., ⁇ 55° C., ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., or ⁇ 5° C.
- the process described herein can further include maintaining the first continuous flow conduit at a temperature of about ⁇ 50° C., ⁇ 40° C., ⁇ 30° C., ⁇ 20° C., or ⁇ 10° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about ⁇ 30° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about ⁇ 35° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of in the range of about ⁇ 100° C. to ⁇ 0° C., ⁇ 90° C. to ⁇ 10° C., ⁇ 80° C.
- the process described herein can further include maintaining the second continuous flow conduit at a temperature in the range of about ⁇ 30° C. to about 40° C., about ⁇ 20° C. to about 30° C., about 0° C. to about 45° C., or about 0° C. to about 25° C.
- the process described herein can further include maintaining the second continuous flow conduit at a temperature of about ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 40° C.
- the process described herein can further include maintaining the second continuous flow conduit at a temperature of about ⁇ 10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature of about 25° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature no greater than 40° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a room temperature. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature in the range of about ⁇ 40° C. to 40° C., ⁇ 30° C.
- the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature in the range of about ⁇ 30° C. to about 30° C., about ⁇ 20° C. to about 20° C., about ⁇ 10° C. to about 20° C., about ⁇ 5° C. to about 20° C., about ⁇ 10° C. to about 10° C., about ⁇ 5° C. to about 5° C., or about 0° C. to about 5° C.
- the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about ⁇ 5° C. to about 10° C.
- the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about ⁇ 30° C., ⁇ 20° C., ⁇ 10° C., ⁇ 5° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 40° C.
- the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of 0° C.
- the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about ⁇ 40° C. to 40° C., ⁇ 30° C.
- the reaction mixture in the vessel can be stirred for at least about 5 min, 20 min, 0.5 h, 1 h, 2 h, 3 h, 5 h, or 12 h. In some embodiments, the reaction mixture in the vessel can be kept stirring at the selected temperature or temperature range for about 5 min-1 h, 5 min-3 h, or 5 min-12 h.
- the process described herein in addition to the step of maintaining the vessel that is downstream of the second continuous flow conduit at a low temperature (e.g, about ⁇ 30° C. to about 30° C., about ⁇ 20° C. to about 20° C., about ⁇ 10° C. to about 20° C., about ⁇ 5° C. to about 20° C., about ⁇ 10° C. to about 10° C., about ⁇ 5° C. to about 5° C., or about 0° C. to about 5° C.), the process described herein also includes a step of warning up the vessel to a room temperature (e.g., 18° C. to 30° C. or 18° C. to 24° C.) and stirring the reaction mixture in the vessel for at least about 5 min, 20 min, 0.5 h, 1 h, 3 h, 5 h, or 12 h.
- a room temperature e.g., 18° C. to 30° C. or 18° C. to 24° C.
- the flow time in the continuous flow conduit can vary depending on the flow rate and the length of the continuous flow conduit.
- a flow time from in the first continuous flow conduit is about 20 s-200 s, about 40 s-about 120 s, about 50 s-100 s, or about 60 s-80 s.
- a flow time in the first continuous flow conduit is about 20 s, 30 s, 40 s, 50 s, 60 s, 70 s, 72 s, 75 s, 80 s, 90 s, 100 s, 110 s, 120 s, 130 s, 140 s, 150 s, 160 s, 170 s, 180 s, 190 s, or 200 s.
- a flow time in the first continuous flow conduit is about 72 seconds. In some embodiments, a flow time in the first continuous flow conduit is in the range of about 10 s-200 s, 20 s-180 s, 20 s-160 s, 20 s-150 s, 20 s-120 s, 20 s-100 s, 20 s-80 s, 30 s-200 s, 30 s-180 s, 30 s-150 s, 30 s-120 s, 30 s-100 s, 30 s-80 s, 40 s-200 s, 40 s-180 s, 40 s-160 s, 40 s-150 s, 40 s-120 s, 40 s-100 s, 40 s-80 s, 50 s-200 s, 50 s-180 s, 50 s-160 s, 50 s-150 s, 50 s-120 s, 50 s-100 s, 50 s-80 s, 50
- a flow time in the second continuous flow conduit is about 5 min to about 30 min, about 10 min to about 25 min, about 12 min to about 20 min, or about 14 min to about 15 min. In some embodiments, a flow time in the second continuous flow conduit is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 min. In some embodiments, a flow time in the second continuous flow conduit is about 14 min. In some embodiments, a flow time in the second continuous flow conduit is about 15 min.
- a flow time in the second continuous flow conduit is in the range of about 1 min-50 min, 1 min-40 min, 1 min-30 min, 1 min-25 min, 1 min-20 min, 1 min-18 min, 1 min-15 min, 3 min-50 min, 3 min-40 min, 3 min-30 min, 3 min-25 min, 3 min-20 min, 3 min-18 min, 3 min-15 min, 5 mm-50 min, 5 min-40 min, 5 min-30 min, 5 min-25 min, 5 min-20 min, 5 min-18 min, 5 min-15 min, 5 min-10 min, 8 min-50 min, 8 min-40 min, 8 min-30 min, 8 min-25 min, 8 min-20 min, 8 min-18 min, 8 min-15 min, 8 min-10 min, 10 min-50 min, 10 min-40 min, 10 min-30 min, 10 min-25 min, 10 min-20 min, 10 min-18 min, 10 min-15 min, or 10 min-12 min.
- reaction mixture of the second reaction intermediate and the compound of Formula (III), which are combined downstream of the second continuous flow conduit are suspended in a vessel and stirred for about 0.5 h-7 h, 1 h-6 h, or about 2 h-5 h. In some embodiments, the mixture of the second reaction intermediate and the compound of Formula (III) are suspended in a vessel and stirred for about 2 h-5 h.
- the concentration of the lithium amide prior to flowing into the first continuous flow conduit can be about 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is about 25%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is lower than 25%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 15% to about 45%, about 15% to 30%, about 15% to about 25%, about 20% to 40%, or about 22% to about 27%.
- the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 25% to about 50%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 20% to about 60%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 1%-100%, 5%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 15%-80%, 15%-70%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-20%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, or 20%-25%.
- the lithium amide solution can be stored in a vessel and the vessel can be pressurized to generate a preferred flow rate for the lithium amide solution flowing out of the vessel.
- the flow rate for the lithium amide solution is in the range of about 0.09 kg/h to about 0.13 kg/h. In some embodiments, the flow rate is in the range of about 0.05 kg/h to about 0.2 kg/h. In some embodiments, the flow rate is in the range of about 0.1 kg/h to about 0.15 kg/h.
- the concentration of the lithium amide in tetrahydrofuran is about 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the concentration of the lithium amide in tetrahydrofuran is about 25%. In some embodiments, the concentration of the lithium amide in tetrahydrofuran is about 15%-30%, about 20%-40%, or about 22% to about 27%.
- the concentration of the lithium amide in tetrahydrofuran is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, or 20%-25%.
- the concentration of the compound of (IIa) or (IIb) prior to flowing into the first continuous flow conduit or in some embodiments is about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%.
- concentration of the lithium amide prior to flowing into the first continuous flow conduit or in some embodiments is about 27%.
- the concentration of the lithium amide prior to flowing into the first continuous flow conduit or in some embodiments is about 45%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 15% to about 75%, about 30% to 50%, about 25% to 50%, or about 40% to about 50%.
- the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- a small amount of trimethylsilyl chloride is added to the solution containing the compound of (IIa) or (IIb) prior to combining the solution with the lithium amide.
- the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is about 0.01, 0.02, 0.03, 0.04, 0.05, or 0.06. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is about 0.03.
- the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is in the range of about 0.01 to 0.1, about 0.02 to about 0.05, or about 0.02 to about 0.04. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is in the range of about 0.001-1, 0.001-0.5, 0.001-0.1, 0.001-0.05, 0.005-1, 0.005-0.5, 0.005-0.1, 0.005-0.05, 0.01-1, 0.01-0.5, 0.01-0.1, 0.01-0.05, 0.02-1, 0.02-0.5, 0.02-0.1, 0.02-0.04, 0.02-0.05, 0.03-1, 0.03-0.5, 0.03-0.1, or 0.03-0.05. In some embodiments, no trimethylsilyl chloride is added to the solution containing the compound of (IIa) or (IIb) prior to combining the solution with the lithium amide.
- the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) can vary depending on the reaction temperature, the reaction solvent, and other reaction conditions in the continuous flow conduit. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is in the range of about 10 to 0.1, about 5 to about 0.5, about 2 to about 0.8, or about 1.5 to about 1.
- the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is about 1.1.
- the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, or 0.75-0.8.
- the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran can vary depending on the reaction conditions. In some embodiments, the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran is about 25%. In some embodiments, the concentration of the lithium amide in the continuous flow prior to combination with the tetrahydrofuran is in the range of about 24% to about 26%. In some embodiments, the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran is in the range of about 15% to about 35%.
- the concentration of the lithium amide in the continuous flow prior to combination with the tetrahydrofuran is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit can vary depending on the reaction conditions. In some embodiments, the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is about 5%, 10%, 20%, 30%, 40%, 45%, 50%, or 60%. In some embodiments, the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is in the range of about 1% to about 80%, bout 10% to about 60%, or about 15% to about 50%.
- the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) can vary depending on the reaction temperature and other reaction conditions in the continuous flow conduit. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) is about 0.5-3, about 0.8-2, or about 1-1.5. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) is about 1-1.5. In some embodiments, the molar ratio of Lewis acid to the compound of Formula (IIa) or (IIb) is higher than about 1.
- the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is about 1.3.
- the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- the concentration of HOBt in the vessel prior to reacting with the compound of formula (VI) may vary depending on the reaction condition.
- the molar ratio of HOBt to the compound of formula (VI) is about 0.5-3, about 0.8-2, or about 0.9-1.1. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 0.8-1.2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is higher than about 1.
- the molar ratio of the HOBt to the compound of formula (IV) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 1.3.
- the molar ratio of HOBt to the compound of formula (VI) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- the concentration of EDC.HCl in the vessel prior to reacting with the compound of formula (VI) may vary depending on the reaction condition.
- the molar ratio of EDC.HCl to the compound of formula (VI) is about 0.5-5, about 0.8-2, or about 0.9-1.5.
- the molar ratio of EDC.HCl to the compound of formula (VI) is about 1-1.5.
- the molar ratio of EDC.HCl to the compound of formula (VI) is higher than about 1.
- the molar ratio of the EDC.HCl to the compound of formula (VI) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 1.6:1.3.
- the molar ratio of HOBt to the compound of formula (VI) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- the amount of the compound of formula (VI) added into the vessel is about 1-1.3 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 0.8-1.6 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 1.1-1.3 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 1.2 molar equivalent of the compound of formula (IIa) or (IIb).
- the amount of HOBt added into the vessel is about 1-1.5 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 0.8-1.8 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 1.2-1.4 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 1.3 molar equivalent of the compound of formula (IIa) or (IIb).
- the amount of EDC.HCl added into the vessel is about 1-2 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 0.5-2.5 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 1.4-1.8 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 1.6 molar equivalent of the compound of formula (IIa) or (IIb).
- the flow rate of the compound of formula (IIa) or (IIb) in the first continuous flow conduit may vary depending on the reaction conditions.
- the process described herein can include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate of about 0.05 mmol/min, 0.1 mmol/min, 0.12 mmol/min, 0.14 mmol/min, 0.16 mmol/min, 0.17 mmol/min, or 0.18 mmol/min.
- the process described herein can further include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate no greater than 0.5 mmol/min, 1 mmol/1, 1.5 mmol/min, 2 mmol/min, 2.5 mmol/min, 3 mmol/min, 3.5 mmol/min, 4 mmol/min, 4.5 mmol/min, or 5 mmol/min.
- the process described herein can further include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate of about 0.1 mmol/min to about 5.0 mmol/min, or about 1 mmol/min to about 3 mmol/min.
- the compound of formula (IIa) or (IIb) flow rate is about 0.05 mmol/min to about 1.2 mmol/min, about 0.05 mmol/min to about 1.0 mmol/min, or 0.1 mmol/min to about 0.5 mmol/min. In some embodiments, the compound of formula (IIa) or (IIb) flow rate is about 0.17 mmol/min.
- the flow rate of the lithium amide in the first continuous flow conduit may vary depending on the reaction conditions.
- the process described herein can include flowing lithium amide into the first continuous flow conduit at a flow rate of about 0.2 mmol/min, 0.4 mmol/min, 0.6 mmol/min, 0.8 mmol/min, 1 mmol/min, 1.2 mmol/min, or 1.5 mmol/min.
- the process described herein can further include flowing the lithium amide into the first continuous flow conduit at a flow rate of about 0.2 mmol/min to about 5 mmol/min, about 0.5 mmol/min to about 2 mmol/min, or about 0.7 to about 0.9 mmol/min.
- the lithium amide flow rate is about 0.87 mmol/min. In some embodiments, the lithium amide flow rate is about 0.9 mmol/min. In some embodiments, the lithium amide flow rate is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.9, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.9, or 0.75-0.8 mmol/min.
- the process described herein can further include flowing the lithium amide into the first continuous flow conduit at a flow rate no greater than 0.5 mmol/min, 1 mmol/l, 1.5 mmol/min, 2 mmol/min, 2.5 mmol/min, 3 mmol/min, 3.5 mmol/min, 4 mmol/min, 4.5 mmol/min, or 5 mmol/min.
- reaction between of the second reaction intermediate with compound of formula (III) is not performed in a continuous flow conduit. In some embodiments, the reaction between of the second reaction intermediate with compound of formula (III) is performed in a flask or other reaction vessel that does not involve continuous flowing.
- the process described herein can also include one or more steps known by those skilled in the art to be suitable for separating and purifying the compound of formula (Ia) or (Ib).
- the separation and/or purification can include extraction, distillation, chromatography, crystallization, and other suitable purifying methods known by those skilled in the art.
- the separation and/or purification can include multiple extraction steps using the same or different solvents in each extraction step, and one or more distillation steps can be used following the extraction to further purify the final product.
- the purification includes a crystallization step.
- the process described herein can further include one or more steps of preparing stock solution of the various reagents.
- the process described herein can further include combining lithium amide and tetrahydrofuran to prepare an lithium amide stock solution for the first continuous flow of the lithium amide.
- the continuous flow of tetrahydrofuran and the continuous flow of the lithium amide are provided separately.
- the process described herein can further include combining the compound of formula (IIa) or (IIb) and tetrahydrofuran to provide the compound of formula (IIa) or (IIb) stock solution for the continuous flow of the compound of formula (IIa) or (IIb).
- the process described herein can further include combining the compound of formula (IIa) or (IIb), tetrahydrofuran, and trimethylsilyl chloride to provide the compound of formula (IIa) or (IIb) stock solution for the continuous flow of the compound of formula (IIa) or (IIb).
- the process described herein can also include pressurizing the vessel containing the stock solutions. In some embodiments, the process described herein includes pressurizing the first or the fifth vessel comprising the lithium amide stock solution. In some embodiments, the process described herein includes pressurizing the second or sixth vessel comprising the compound of formula (IIa) or (IIb) stock solution. In an embodiment wherein the continuous flow of tetrahydrofuran and the continuous flow of the lithium amide are provided separately, the process described herein can further include preparing a stock solution of the lithium amide in tetrahydrofuran and pressurizing a vessel comprising the lithium amide in tetrahydrofuran stock solution. In such an embodiment, the process described herein can further include preparing a stock solution of tetrahydrofuran and pressurizing a vessel comprising the tetrahydrofuran stock solution.
- the process includes producing the compound of Formula Ia.
- M is —CH ⁇ CH— and n is 1.
- M is —CH 2 — and Q is —CH 2 — or —CH 2 —CH 2 —.
- the process includes producing the compound of Formula (Ib) or salt thereof.
- the compound of Formula Ia is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
- the compound of Formula (IIa) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-N-phenyl
- the process described herein can further include performing the reaction of the compound of formula (III) and the second reaction intermediate under a nitrogen or argon atmosphere.
- the process described herein can further include analyzing a reaction flow sample taken after the first continuous flow conduit but before the second continuous flow conduit. In some embodiments, the process described herein can further include analyzing a reaction flow sample taken after the second continuous flow conduit but before the vessel that contains the compound of formula (III).
- reaction samples can be performed using any suitable known analytic methods.
- the process described herein includes analyzing the reaction sample using a chromatography.
- the process described herein includes analyzing the reaction sample using a HPLC.
- the process described herein can be used for production of the compound of formula (Ia) or (Ib) on a plant scale or pilot plant scale.
- the process described herein can be used to produce over about 10 kg, 20 kg, 50 kg, 80 kg, 100 kg, 150 kg, 180 kg, or 200 kg of the compound of formula (Ia) or (Ib) per day.
- an additional flow for THE can be introduced to have better control over lithium amide concentration and stoichiometry and help enhance process robustness by prevention blocking of the LT tube reactor by precipitation of the lithium amide.
- compound (IIa) or (IIb) concentration can be reduced or adjusted based on the lithium amide concentration in the flow after the dilution using an additional flow of THF.
- the dilution using an additional flow of THE can help ensure higher yield and better conversion of raw materials comparative to other known process.
- the continuous flow conduit including the first and the second continuous flow conduit, can be lengthened so increase the residence time to an extent that additional stirring in collection vessel at ambient temperature is no longer required to achieve full conversion of starting material compound of formula (IIa) or (IIb). This can help simply the process, shorten the production time, and save the use of any stirring vessel.
- full conversion of the starting material compound of formula (IIa) or (IIb) can be achieved in the process and the second reaction intermediate (e.g., compound 2d) can be directly delivered to the solution containing the active ester compound of formula (III).
- the second reaction intermediate e.g., compound 2d
- the amount of impurity compound resulted from lithium amide side reaction is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, 0.25% or 0.1% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 5% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 1.4% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g.).
- compound S1 or S2 is less than about 1% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 0.9% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is in the range of about 0.1% to about 10%, about 0.1% to about 5%, about 0.15 to about 1.0% in the final product.
- the amount of the diastereomer of the compound of formula (Ia) or (Ib) is less than about 1% in the final product. In some embodiments, the amount of the diastereomer of the compound of formula (Ia) or (Ib) is less than about 0.9%, 0.8%, 0.6%, 0.4%, 0.2%, or 0.1% in the final product. In some embodiments, the amount of the diastereomer of the compound of formula (Ia) or (Ib) is in the range of about 0.1% to about 10%, about 0.1% to about 5%, about 0.15 to about 1.0% in the final product.
- the amount of total impurities is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, 0.25% or 0.1% in the final product. In some embodiments, the amount of total impurities is less than about 8% in the final product. In some embodiments, the amount of total impurities is less than about 1.7% or 1.6% in the final product. In some embodiments, the amount of total impurities is less than about 1.4% in the final product. In some embodiments, the amount of total impurities is less than about 1.33% in the final product. In some embodiments, the amount of total impurities is in the range of about 0.1% to about 10%, about 0.1% to about 8%, about 0.15 to about 1.6% in the final product.
- the amount of compound A diastereomer is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.08%, 0.07%, 0.06%, 0.04%, 0.025% or 0.01% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.4% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.07% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.05% in the final product. In some embodiments, the amount of compound A diastereomer is in the range of about 0.001% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.4% in the final product.
- the amount of any single unknown impurity is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.08%, 0.07%, 0.06%, 0.04%, 0.025% or 0.01% in the final product.
- the amount of any single unknown impurity is less than about 0.4% in the final product.
- the amount of any single unknown impurity is less than about 0.07% in the final product.
- the amount of any single unknown impurity is less than about 0.05% in the final product.
- the amount of any single unknown impurity is in the range of about 0.001% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.4% in the final product.
- FIG. 1 is a non-limiting schematic of an apparatus for a continuous production process as described herein.
- FIG. 1 shows an apparatus 100 for production of a compound of Formula (Ia) or (Ib) or salt thereof,
- FIG. 2 is a non-limiting schematic of an apparatus for a continuous production process as described herein.
- FIG. 2 shows an apparatus 200 for production of a compound of Formula Ia or Ib or salt thereof,
- the apparatus described herein can optionally include one or more vessels containing the stock solutions of one or more reagents.
- the apparatus described herein can further include a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit.
- the apparatus described herein can include a fifth flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit.
- the apparatus described herein can include optionally a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit, and wherein the third continuous flow conduit is configured to deliver the lithium amide from the first vessel to the first continuous flow conduit.
- the apparatus described herein can optionally include a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit, and wherein the fourth continuous flow conduit is configured to deliver the compound of formula (IIa) or (IIb) from the second vessel to the first continuous flow conduit.
- the apparatus described herein can include a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit, and wherein the fourth continuous flow conduit is configured to deliver the compound of formula (IIa) or (IIb) and/or trimethylsilyl chloride from the second vessel to the first continuous flow conduit.
- the apparatus described herein can optionally include a fifth continuous flow conduit to fluidly couple the fourth vessel and the first continuous flow conduit, and wherein the fifth continuous flow conduit is configured to deliver the tetrahydrofuran solution from the fourth vessel to the first continuous flow conduit.
- the apparatus described herein can optionally further include a sixth vessel fluidly coupled to the first vessel, wherein the sixth vessel comprises a stock solution of the lithium amide.
- the apparatus described herein can optionally further include a seventh vessel fluidly coupled to the second vessel, wherein the seventh vessel comprises a stock solution of the compound of Formula (IIa) or (IIb).
- the apparatus described herein can optionally further include an eighth vessel fluidly coupled to the second vessel, wherein the eighth vessel comprises a stock solution of the compound of trimethylsilyl chloride.
- One or more flow control members can be used in the apparatus to control the flow rate.
- the apparatus described herein can further include one or more flow control members fluidly coupled to the vessels comprising stock solutions of the lithium amide, tetrahydrofuran, trimethylsilyl chloride, or the compound of formula (IIa) or (IIb).
- the flow control members can be a pneumatic flow control including but not limited to a pressurized vessel; a valve; any pump known to be suitable for flow control, including but not limited to a syringe pump; any other flow control equipment known in the art; and combinations thereof.
- the vessel containing a stock solution can be pressurized depending on the flow control member used in the apparatus. In an embodiment wherein a valve is used to control the flow rate, a pressurized vessel containing a stock solution instead of a pump can be used in the apparatus described herein.
- the vessel which comprises a stock solution of the lithium amide can be pressurized.
- the vessel which comprises a stock solution of the compound of formula (IIa) or (IIb) can be pressurized.
- the vessel which comprises a stock solution of the trimethylsilyl chloride compound can be pressurized.
- the first vessel is pressurized.
- the second vessel is pressurized.
- the third vessel is pressurized. In some embodiments, the fourth vessel is pressurized. In some embodiments, the fifth vessel is pressurized. In some embodiments, the sixth vessel is pressurized. In some embodiments, the seventh vessel is pressurized. In some embodiments, the eighth vessel is pressurized.
- the first vessel 101 is fluidly coupled to the first continuous flow conduit 103 through a valve 101 a
- the second vessel 102 is fluidly coupled to the continuous flow conduit 103 through a valve 102 a
- an additional vessel, the fourth vessel 206 for the tetrahydrofuran can be fluidly coupled to the first continuous flow conduit through a valve 206 a.
- One or more vessels in the apparatus can be a continuous flow conduit.
- the first vessel 101 or 201 can optionally include a third continuous flow conduit, wherein the third continuous flow conduit is fluidly coupled with the first continuous flow conduit 103 or 203 to help deliver the solution in the first vessel 101 or 201 into the first continuous flow conduit 103 or 203 .
- the second vessel 102 or 202 can optionally include a fourth continuous flow conduit, wherein the fourth continuous flow conduit is fluidly coupled with the first continuous flow conduit 103 or 203 to help deliver the solution in the second vessel 102 or 202 into the first continuous flow conduit 103 or 203 .
- the third vessel 105 or 205 can optionally include a fifth continuous flow conduit, wherein the fifth continuous flow conduit is fluidly coupled with the second continuous flow conduit 104 or 204 to help flow the solution in the second continuous flow conduit 104 or 204 into the third vessel 105 or 205 .
- the first vessel 101 or 201 does not contain a continuous flow conduit.
- the second vessel 102 or 202 does not contain a continuous flow conduit.
- the third vessel 105 or 205 does not contain a continuous flow conduit.
- the fourth vessel 206 can optionally include a continuous flow conduit. In some embodiments, the fourth vessel 206 does not have a continuous flow conduit.
- the fifth vessel can optionally include a continuous flow conduit.
- the fifth vessel is fluidly coupled to the first vessel and the fifth vessel comprises a stock solution of the lithium amide.
- the sixth vessel can optionally include a continuous flow conduit.
- the sixth vessel is fluidly coupled to the second vessel and the sixth vessel comprises a stock solution of the compound of formula (IIa) or (IIb).
- the seventh vessel can optionally include a continuous flow conduit.
- the seventh vessel is fluidly coupled to the second vessel and the seventh vessel comprises a stock solution of the trimethylsilyl chloride.
- the eighth vessel can optionally include a continuous flow conduit.
- the eighth vessel is fluidly coupled to the third vessel and the eighth vessel comprises a stock solution of tetrahydrofuran.
- the apparatus described herein can further include one or more cooling elements.
- the cooling elements are thermally coupled to the first continuous flow conduit 103 or 203 .
- the cooling elements are thermally coupled at least one of the first continuous flow conduit 103 or 203 , the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit.
- the cooling elements are thermally coupled at least one of the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit.
- the apparatus described herein can further include one or more cooling elements thermally coupled to at least one of the first vessel 101 or 201 , the second vessel 102 or 202 , the third vessel 105 or 205 , and/or the fourth vessel 206 .
- the apparatus described herein can further include a cooling element thermally coupled to the fourth vessel 106 or 206 .
- the apparatus described herein can optionally further include a cooling element thermally coupled to the fifth, sixth, and seventh vessels.
- the apparatus described herein can further include a cooling element thermally coupled to the alkyl amide solution vessel and the tetrahydrofuran solution vessel.
- the apparatus described herein can further include one or more heating elements.
- the heating element is used to warm up the reaction mixture that flows out of the first continuous flow conduit 103 or 203 .
- the heating elements are thermally coupled to the second continuous flow conduit 104 or 204 .
- the heating elements are thermally coupled to the third vessel 105 or 205 .
- the heating element can be any suitable heating equipment known in the art.
- the apparatus described herein can further include a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere.
- the continuous flow conduit can be made of any suitable materials known in the art for conducting chemical reactions performed under low temperatures.
- the continuous flow conduit can be made of stainless steel.
- the first and second continuous flow conduits are made of stainless steel.
- the first, the second, the third, and the fourth vessels are made of stainless steel.
- the third vessel 105 or 205 is not a continuous flow conduit. In some embodiments, the third vessel 105 or 205 can be a flask or a reaction vessel that does not involve the reaction mixture flowing out of the flask or reaction vessel.
- the dimension of the continuous flow conduit can vary depending on the reaction conditions and the production scale.
- Each continuous flow conduit can have a size that is different from or same as the other continuous flow conduit.
- the continuous flow conduit is made of a tubing having a length in the range of about 0.1 m to about 50 m, about 0.1 m to about 25 m, or about 0.1 m to about 10 m.
- the tubing can be of straight or spiral.
- the apparatus described herein can include one or more valves positioned following the continuous flow conduit. In some embodiments, the apparatus described herein includes a valve immediately downstream of the first continuous flow conduit. In some embodiments, the apparatus described herein includes a valve immediately downstream of the second continuous flow conduit.
- the apparatus described herein can further include one or more flow control members fluidly coupled to the first, the second, the third, the fourth, the fifth, the sixth, or the seventh vessel.
- the flow control member is fluidly coupled to the input of the first, the second, or the third vessel.
- the flow control member is fluidly coupled to the output of the first, the second, or the third vessel.
- the flow control member is fluidly coupled to at least one of the first, the second, and the third vessels.
- the flow control member is fluidly coupled to the output of the fifth, sixth, or seventh vessel.
- the flow control member is fluidly coupled to the input of the fourth vessel.
- the apparatus here is used for the production of the compound of Formula (Ia). In some embodiments, the apparatus here is used for the production of the compound of Formula (Ib).
- the second vessel includes the compound of Formula (IIa). In some embodiments, the second vessel includes the compound of Formula (IIb).
- the apparatus described herein can be used for production of the compound of formula (Ia) or (Ib) on a plant scale.
- the apparatus described herein can be used to produce more than about 10 kg, 100 kg, 250 kg, 500 kg, 800 kg of the compound of formula (Ia) or (Ib) per day.
- Method B-2 Method A-1 and B-1: Compound A wt %, % a Final Product: Compound 2a wt % (derivatization, HPLC compound A wt %, % a (HPLC-CAD) UV) (HPLC UV)
- Compound 2e For preparation of Compound 2e, a slurry of purified 2-thiophen-acetic acid and hydroxybenzotriazole in acetonitrile was pre-cooled to ⁇ 5 to 5° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI) was added in portions in a way that the temperature can be maintained at ⁇ 5 to 5° C.
- EDC.HCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
- the experimental set-up 100 as schematically outlined in FIG. 1 was used.
- a first vessel 101 is used for storing and providing the lithium bis(trimethylsilyl)amide solution (in THF)
- a second vessel 102 is used for storing and providing a compound 2a solution in tetrahydrofuran.
- a first continuous flow conduit 103 is used for mixing the lithium bis(trimethylsilyl)amide and compound 2a reagents and for delivering the reaction mixture to the next step.
- a second continuous flow conduit 104 is used to warm up the reaction mixture that flows out of the first continuous flow conduit 103 and to deliver the reaction mixture to the next step.
- a vessel 105 is used for carrying out the reaction of making compound 2e and for collecting the compound 2d that flows out of the second continuous flow conduit 104 so that compound 2e and compound 2d can react to form compound A.
- the lithium bis(trimethylsilyl)amide stock solution in THF was continuously added into the reaction process from the vessel 101 through a valve 101 a and the lithium bis(trimethylsilyl)amide was pre-cooled before reaching the first continuous flow conduit 103 ; a compound 2a stock solution in THE was continuously added into the reaction process from the vessel 102 through a valve 102 a ; the mixture of lithium bis(trimethylsilyl)amide and compound 2a continuously flowed through the first continuous flow conduit 103 , which was maintained at about ⁇ 30° C. using a cooling bath 106 .
- the reaction mixture flowed from the first continuous conduit 103 to the second continuous flow conduit 104 , which was maintained at an ambient temperature or maintained between 20° C.-30° C.
- a valve such as 101 a , 102 a , or 104 a can be used to fluidly couple to a vessel or to a continuous flow conduit to control the flow of the reaction solutions.
- the set-up may include only one of the three valves 101 a , 102 a , and 104 a ; the set-up may include any two of the three valves 101 a , 102 a , and 104 a ; or the set-up may include all three valves 101 a , 102 a , and 104 a .
- An additional valve 103 a may be optionally added between the first continuous flow conduit and the second continuous flow conduit.
- the set-up shown in FIG. 2 can optionally include one or more other valves (not shown in the figure) to control the flow of the reaction at one or more other points in the set-up.
- the set-up was operated at constant flows and a cooling bath was used to pre-cool the solutions and to maintain the needed reaction temperature.
- the first part of the set-up (for LHMDS addition) was operated at low temperature (low temperature flow reactor). Sections of the set-up, including the tubes for delivering the lithium bis(trimethylsilyl)amide and/or the compound 2a solution were pre-cooled to guarantee fast mixing of the two flows and an efficient heat transfer.
- the second part of the flow reactor, (for rearrangement reaction) was operated at elevated temperature (in this case at room temperature—RT flow reactor). The key element of this set-up was to warm up the reaction solution to target temperature.
- a method B (B-1) sample can be pulled after the low temperature reactor run to check the conversion rate.
- method B was introduced: The method A sample was converted to the second reaction intermediate using the active ester and the sample was analyzed after completed amidation (in this case derivatization). This method gives an overview about the expected product quality and yield after the rearrangement reaction.
- the experimental set-up 100 as schematically outlined in FIG. 1 was used.
- the vessel 101 for storing and providing lithium bis(trimethylsilyl)amide (25% in THF) was set to be about 1.5-1.0 mol eq. of compound 2a.
- the vessel 102 for compound 2a was diluted with THE to a final concentration of 27 w %.
- Both lithium bis(trimethylsilyl)amide and compound 2a solutions were precooled to the operating temperature “low temperature” of about ⁇ 30° C. continuous flow conduit.
- the low temperature continuous flow conduit had a length of 12 m, diameter of 0.88 cm, which corresponded to a residence time of about 70 sec.
- the room temperature continuous flow conduit had a length of 12 m, diameter of about 1.73 cm, which corresponded to a residence time of 4.5 min.
- Two additional vessels (not shown in FIG. 1 ) were installed after the continuous flow conduit: one each for pre- and post-run (start and Shutdown sequence). The first vessel was used for collecting waste at the beginning of the run until all flows were properly established. The second vessel was used in case of a problem such as clogging, in which case an automatic shutdown sequence would be triggered. In the event of clogging, the flow would be diverted to the second vessel so that the product collected up to that point would not be contaminated.
- the reaction mixture was delivered to the vessel 105 and was stirred with compound 2e at room temperature.
- Two sample valves 103 a and 104 a were installed for taking samples for chromatography analysis of the reaction conversion, with one valve 103 a after the first continuous flow 103 conduit and one valve 104 a after the second continuous flow conduit 104 .
- reaction mixture was stirred for 10 min in the collection vessel, and sample analysis showed a typical impurity profile, meaning that no unknown impurities were detected. Analysis of samples taken after the first continuous flow conduit using method A showed a very small amount of compound 2a remaining. Results of the residual amount of compound 2a detected in the process are shown in Table 2.
- the experimental set-up 200 as schematically outlined in FIG. 2 was used.
- a first vessel 201 is used for storing and providing the lithium bis(trimethylsilyl)amide solution (in THF)
- a second vessel 202 is used for storing and providing a compound 2a solution in tetrahydrofuran.
- a first continuous flow conduit 203 is used for mixing the lithium bis(trimethylsilyl)amide and compound 2a reagents and for delivering the reaction mixture to the next step.
- a second continuous flow conduit 204 is used to warm up the reaction mixture that flows out of the first continuous flow conduit 203 and to deliver the reaction mixture to the next step.
- a vessel 205 is used for carrying out the reaction of making compound 2e and for collecting the compound 2d that flows out of the second continuous flow conduit 204 so that compound 2e and compound 2d can react to form compound A.
- An additional vessel 206 is used for storing and providing a separate stream THE solution to be combined with the lithium bis(trimethylsilyl)amide solution (in THF).
- the lithium bis(trimethylsilyl)amide stock solution in THF was continuously added into the reaction process from the vessel 201 through a valve 201 a and a separate THE stock solution was stored in vessel 206 and was continuously added into the reaction process to dilute the lithium bis(trimethylsilyl)amide in the flow stream before lithium bis(trimethylsilyl)amide was mixed with the compound 2a.
- the diluted lithium bis(trimethylsilyl)amide solution was pre-cooled to ⁇ 30° C. before reaching the first continuous flow conduit 203 .
- the compound 2a stock solution in THE was continuously added into the reaction process from the vessel 202 through a valve 202 a ; the mixture of lithium bis(trimethylsilyl)amide (diluted) and compound 2a continuously flowed through the continuous flow conduit 203 , which was is maintained at about ⁇ 30° C. using a cooling bath 207 .
- the reaction mixture flowed from the first continuous conduit 203 to the second continuous flow conduit 204 , which was maintained at an ambient temperature or maintained between 20° C.-30° C. using a bath 208 .
- the second continuous flow conduit 204 was used to warm up the reaction mixture that flowed out of the first continuous flow conduit 203 .
- the reaction mixture was then delivered to a vessel 205 .
- the vessel 205 was maintained at ⁇ 5° C.
- a valve such as 201 a , 202 a , 204 a, 206 a can be used to fluidly couple to a vessel or to a continuous flow conduit to control the flow of the reaction solutions.
- the set-up may include only one of the four valves 201 a , 202 a , 204 a , and 206 a ; the set-up may include any two of the four valves 201 a , 202 a , 204 a , and 206 a ; the set-up may include any three of the four valves 201 a , 202 a , 204 a , and 206 a ; or the set-up may include all four valves 201 a , 202 a , 204 a , and 206 a .
- An additional valve 203 a may be optionally added between the first continuous flow conduit and the second continuous flow conduit.
- the set-up shown in FIG. 2 can optionally include one or more other valves (not shown in the figure) to control the flow of the reaction at other points in the set-up.
- the flow setting was set to have the lithium bis(trimethylsilyl)amide to be 1.10 eq. of compound 2a, and the lithium bis(trimethylsilyl)amide (LHDMS) had a concentration of 17% after mixing with the separate steam of THF. A higher level of LHMDS with a molecular ration of 1.18 eq of compound 2a was also tested. Table 3 shows the results of the process with THE introduced to dilute the lithium amide.
- the samples were converted to the final product using the active ester compound 2e to evaluate the product quality and impurity profile of the final product compound A.
- sample derivatization the same stoichiometry and reaction conditions were used as for the batch compound A synthesis, and the product was analyzed from solution after amidation.
- the small-scale derivatization procedure for analysis method A shown in Table 1 was used, and samples were then compared to the data from the isolated product.
- lithium bis(trimethylsilyl)amide may lead to an increase in the amount of by-product formed.
- One by-product can be formed via ⁇ -deprotonation followed by elimination when excessive lithium bis(trimethylsilyl)amide is used.
- This by-product compound S1 is depleted by approx. 70% in the crystallization step of compound A.
- the presence of increased amounts of the by-product can lead to difficulties in the crystallization of compound A and have therefore a strong influence on product yield.
- Another by-product resulting from the use of high concentration or excess of lithium salt such as (t-butyl lithium) may include the compound S2:
- Diluting the lithium amide flow with an additional stream of THE can help provide better control over the lithium amide concentration and stoichiochemistry. It also can help to enhance process robustness by preventing precipitation of LHMDS from blocking the continuous flow conduit.
- the experimental set-up as schematically outlined in FIG. 1 was used except that the residence time in the second continuous flow conduit was adjusted in the continuous flow process.
- the residence time in the second continuous flow conduit (room temperature) was compared at 4.5 min and about 15 min.
- the results showed that having a residence time of 15 mins in the second continuous flow conduit increased the conversion rate and the yield of compound A.
- the results also indicated that the synthesis of compound 2d in the continuous flow conduits can achieve full conversion and did not require an additional collecting vessel or stirring time at ambient temperature.
- the direct conversion of compound 2d to compound A can be achieved by collection of compound 2d in the active ester compound 2e solution in the vessel 205 . This process leads to reduction of reaction time, simplifying the process, and increasing the overall productivity.
- the values in the process were based on 45 g compound 2a, which equaled to a 20 min run (the vessels 101 , 102 , 105 , and 106 were filled with an excess of solution to account for start-up and shut-down sequence). For comparison reason, the given values were based on steady state of the reaction.
- the amount of compound A obtained was about 18.07 g, and the yield based on HPLC analysis is about 72.89%.
- the purity of the final product compound A, based on HPLC analysis was about 99.9%.
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Abstract
A process for a continuous production of a boronic acid derivative and an apparatus of performing the process are disclosed.
Description
- This application is a divisional of U.S. patent application Ser. No. 16/482,195, filed Jul. 30, 2019, which is a National Stage Entry of PCT International Application Number PCT/US2018/016246, filed Jan. 31, 2018, which claims the benefit of priority to U.S. Provisional Patent Application No. 62/453,408, filed Feb. 1, 2017, each of which is incorporated by reference in its entirety for all purposes.
- This invention was made with Government support under contract HHSO100201400002C awarded by the U.S. Department of Health and Human Services. The Government has certain rights in the invention.
- The present disclosure relates to a continuous flow process for production of boronic acid derivatives and apparatus of performing the same. More particularly, it relates to a continuous flow process for a large scale production of boronic acid derivatives.
- Boronic acid derivatives are useful as potentiators of antimicrobial compounds. Some methods for α-acylamidoboronic ester synthesis include the addition of the lithium salt of an amine and rearrangement followed by an amide coupling reaction. However, maintenance of low temperature, exclusion of water and careful control of stoichiometry of the reagents are required for good results. These features render the reaction difficult to perform successfully on a production scale, and limit the availability of pharmaceutically important boronic ester and acid compounds. Thus, there remains a need for a process for the easy scale-up production of α-acylamidoboronic acid derivatives.
- Some embodiments relate to a process for production of a compound of Formula (Ia) or (Ib) or salt thereof,
-
- wherein:
- Q is —(CH2)m—;
- M is —CH2— or —CH═CH—;
- m is 1 or 2;
- R1 is a carboxyl protecting group;
- R2 is a hydroxyl protecting group; or
- R1 and R2 together with the atoms to which they are attached form a five-member heterocyclic ring optionally substituted with C1-4 alkyl;
- each R3 is independently selected from hydrogen, —OH, halogen, —CF3, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, cyano, C1-C6 alkoxy(C1-C6)alkyl, C6-10 aryloxy, sulfhydryl (mercapto), and —(CH2)m—Y′—(CH2)pM′;
- m and p are independently 0 to 3;
- Y′ is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CR4aR5a—, and —NR1a—;
- M′ is selected from the group consisting of —C(O)NR1aR2a; —C(O)NR1aOR3a; —NR1aC(O)R4a; —NR1C(O)NR2aR1b; —NR1C(O)OR3a; —NR1S(O)2R3a; —NR1aS(O)2NR2aR1b; —C(═NR1a)R4a; —C(═NR1a)NR2aR1b; —NR1aCR4a(NR2a); —NR1aC(═NR2a)NR1bR2b; C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a;
- each R1a, R2a, R1b and R2b are independently selected from the group consisting of —H, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
- R3a is hydrogen, optionally substituted C1-10alkyl, -optionally substituted C1-10alkyl-COOH, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl; and
- each R4a and R5a is independently selected from the group consisting of —H, —OH, -optionally substituted alkoxyl, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
- n is 0 to 3;
- G is selected from the group consisting of —NR1R2, —N3, —C(O)NR1R2, —S(O)2NR1R2, —SR3, —OR3, —NR1C(O)R5, —C(═NOR3)—X, C(═NOR3)—Z, —C(O)OR3, —C(O)NR1(OR3), —NR1(OR3), —NR1C(O)R5, —NR1C(O)NR2R1a, —NR1C(O)OR3, —NR1S(O)2R3, —NR1S(O)2NR2R1a, —NR1NR2R1a, —C(O)NR1NR2R1a, —S(O)2NR′NR2R1a, —C(═NR1)R5, —C(═NR1)NR2R1a, —NR1CR5(═NR2), —NR1C(═NR2)NR1aR2a, optionally substituted C1-10 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6alkylene-C3-7carbocyclyl, optionally substituted C1-6alkylene-5-10 membered heterocyclyl, optionally substituted C1-6alkylene-C6-10aryl, and optionally substituted C1-6alkylene-5-10 membered heteroaryl;
- X is hydrogen or optionally substituted C1-9alkyl;
- Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
- the process comprising:
- providing a continuous flow of a lithium amide;
- providing a continuous flow of a compound of Formula (IIa) or (IIb) or salt thereof;
-
- combining the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb) at a first continuous flow conduit at a first temperature to yield a first reaction intermediate;
- transitioning the first reaction intermediate to a second temperature to yield a second reaction intermediate; and
- combining the second reaction intermediate and a compound of Formula (III) downstream of the second continuous flow conduit to yield the compound of Formula (Ia) or (Ib) or salt thereof
-
A-O—C(O)—(CH2)nG (III) -
- wherein A is a C6-10aryl, 5-10 membered heteroaryl, C3-7carbocyclyl, or 5-10 membered heterocyclyl.
- Some embodiments relate to an apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof,
-
- the apparatus comprising:
- a first vessel comprising a lithium amide;
- a second vessel comprising a compound of Formula (IIa) or (IIb) or salt thereof;
-
- a third vessel comprising a compound of Formula (III) or salt thereof;
-
A-O—C(O)—(CH2)nG (III) -
- wherein A is a C6-10aryl, 5-10 membered heteroaryl, C3-7carbocyclyl, or 5-10 membered heterocyclyl;
- a first continuous flow conduit fluidly coupled to the first vessel and the second vessel; and
- a second continuous conduit fluidly coupled between the first continuous flow conduit and the third vessel.
-
FIG. 1 illustrates a non-limiting schematic of a continuous flow apparatus. -
FIG. 2 illustrates a non-limiting schematic of a continuous flow apparatus. - The disclosed technology relates to a continuous flow process for the production of boronic acid derivatives. The process allows a continuous production of boronic acid derivatives with a high yield and simplified steps. In particular, the process specifically provides for the production of a key reaction intermediate in a process to prepare useful boronic acid derivatives. In some embodiments, the reaction intermediate has the structure of Compound A:
- The batch process for the synthesis of Compound A involves a LHMDS mediated addition/arrangement reaction of compound 2a, followed by an EDCl/HOBt mediated amide coupling reaction of compound 2d with an ester (e.g., a thienylacetic acid compound 2e) as shown in Scheme 1.
- The continuous process described herein allows for continuous synthesis of a first reaction intermediate (e.g., compound 2b) and a second reaction intermediate (e.g., compound 2d), with a high or full conversion of the starting reagent, the compound of formula (IIa) or (IIb) (e.g. compound 2a). Because of the full conversion of the starting reagent (e.g. compound 2a), the continuous flow containing the second reaction intermediate (e.g., compound 2d) can be added directly into a vessel that has a compound of formula III (e.g., compound 2e) or the reagents used to make a compound of formula III (e.g., HOBt/EDCl mediated amidation with a 2-thienylacetic acid for making compound 2e). Therefore, the process described herein allows for synthesis of compound A from the starting material compound of formula (IIa) or (IIb) without the need to separate or purify the reaction intermediate or the compound of formula III (e.g., the reaction intermediate compound 2d and/or the compound of formula III). This process and apparatus for conducting this process simplifies the synthesis steps and leads to an increased productivity. They also lead to better scalability, energy efficiency, shorter production time, and fewer reaction vessels required.
- Some embodiments include production of the second reaction intermediate (e.g., compound 2d) and the compound of formula (III) (e.g., compound 2e) in parallel, which can then be reacted together to produce a compound of formula (Ia) or (Ib) (e.g. Compound A) without the need to purify each compound prior to reaction. The process described herein leads to better scalability and energy efficiency as well as saving reaction time and reaction vessels. In some embodiments, the process operates under cryogenic conditions; however, reaction temperatures below −70° C. used for batch production can be avoided. In some embodiments, temperatures of −30° C. can be used to provide a more readily scalable process with better reproducibility and higher yield. In some embodiments, the compound of formula (IIa) or (IIb) (e.g., compound 2a) could be driven to full conversion, and the reaction flow carrying the second reaction intermediate (e.g., compound 2d) can be directly added to a reaction vessel in which the compound of formula (III) is made without the need to purify the second reaction intermediate or the compound of formula (III) prior to reaction of the two together.
- The chiral boronic ester compound A is an intermediate in the synthesis of Compound B, a β-lactamase inhibitor.
- In a batch process, all the operations are performed in successive steps using one or more reactors, and the increase in production scale in a batch production often results in lower yield, higher level of impurities, and poor reproducibility and selectivity for stereoisomers. In addition, large reactor volumes also may correspond to increase in capital investments.
- In a continuous process, separate continuous flow conduits are used for each step of the reaction, and the reaction mixture flows from one operation to the next within the production line. The operations are performed continuously and some of the reaction parameters such as flow rate, molar ratio, and reaction temperatures can be easily and quickly adjusted based on a concurrent monitoring of the reaction product. Consequently, a continuous production process requires much smaller equipment volumes for achieving the same production capacity. In addition, a continuous operation helps to ensure the quality of the product. Moreover, a continuous flow process may be preferable over a traditional batch process as it would mitigate the risks that are associated with potentially hazardous decomposition or other side reactions of the lithium amide. The shorter residence times in continuous flow set-up can allow operation at higher temperatures. Furthermore, the continuous process described herein achieves full or near full conversion of the second reaction intermediate, which makes it possible to add the continuous flow containing the second reaction intermediate directly to the vessel containing the compound of Formula (III) without any purification or separation of the second reaction intermediate.
- A continuous flow process and the apparatus for performing the continuous flow process are often complicated to design and highly specific to the types of reaction product and production rate. The continuous flow process described herein, by utilizing a continuous flow process to produce a reaction intermediate and performing the last amidation step in a non-continuous-flow vessel, has shown great reproducibility and high yield as compared to the other types continuous flow processes that involve performing the last quenching step inside a continuous flow conduit. Additionally, the continuous flow process described herein has allowed successful production of the compound of formula I, particularly compound A in a large scale with a high yield.
- The term “substantially free of water” as used herein means a product has been dried using standard techniques known in the art. In some embodiments, “substantially free of water” means the product contains less than 0.5%, 1%, 3%, or 5% of water. In some embodiments, “substantially free of water” means the product contains less than 0.1% of water or no water.
- The term “continuous flow conduit” as used herein refers to any pipe, tube, channel, channeled plate, or any other vessel of suitable shape for conveying fluids in a continuous flow process.
- The term “residence time” as used herein refers to the time required for the reaction mixture or stock solution to flow from the input to the output of a continuous flow conduit.
- The term “thermally coupled” as used herein refers to a direct or indirect coupling between two objects in way that facilitates heat transfer between the two objects. For example, when a vessel or continuous flow conduit is thermally coupled to a cooling bath, the vessel or continuous flow conduit can be immersed in the cooling bath to achieve a desired temperature.
- The term “fluidly coupled” as used herein means that a first component are in fluid communication with another component. Such fluid communication may be achieved by either direct or indirect connection via valves, pipes, conveyors, pumps, conduits and any other suitable connectors known by those skilled in the art.
- As used herein, “Ca to Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in the specified group. That is, the group can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” or “C1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3—, CH3CH2—, CH3CH2CH2—, (CH3)2CH—CH3CH2CH2CH2—, CH3CH2CH(CH3)— and (CH3)3C—.
- The term “halogen” or “halo,” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.
- As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 9 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of the compounds may be designated as “C1-4 alkyl” or similar designations. By way of example only, “C1-4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.
- As used herein, “alkoxy” refers to the formula —OR wherein R is an alkyl as is defined above, such as “C1-9 alkoxy”, including but not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy, and the like.
- As used herein, “alkylthio” refers to the formula —SR wherein R is an alkyl as is defined above, such as “C1-9 alkylthio” and the like, including but not limited to methylmercapto, ethylmercapto, n-propylmercapto, 1-methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec-butylmercapto, tert-butylmercapto, and the like.
- As used herein, “alkenyl” refers to a straight or branched hydrocarbon chain containing one or more double bonds. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group of the compounds may be designated as “C2-4 alkenyl” or similar designations. By way of example only, “C2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2,-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.
- As used herein, “alkynyl” refers to a straight or branched hydrocarbon chain containing one or more triple bonds. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of the compounds may be designated as “C2-4 alkynyl” or similar designations. By way of example only, “C2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.
- As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group could also be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of the compounds may be designated as “C1-4 heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C1-4 heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.
- The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of atoms) groups provided that the entire ring system is aromatic.
- As used herein, “aryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent carbon atoms) containing only carbon in the ring backbone. When the aryl is a ring system, every ring in the system is aromatic. The aryl group may have 6 to 18 carbon atoms, although the present definition also covers the occurrence of the term “aryl” where no numerical range is designated. In some embodiments, the aryl group has 6 to 10 carbon atoms. The aryl group may be designated as “C6-10 aryl,” “C6 or C10 aryl,” or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, and anthracenyl.
- As used herein, “aryloxy” and “arylthio” refers to RO— and RS—, in which R is an aryl as is defined above, such as “C6-10 aryloxy” or “C6-10 arylthio” and the like, including but not limited to phenyloxy.
- An “aralkyl” or “arylalkyl” is an aryl group connected, as a substituent, via an alkylene group, such “C7-14 aralkyl” and the like, including but not limited to benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).
- As used herein, “heteroaryl” refers to an aromatic ring or ring system (i.e., two or more fused rings that share two adjacent atoms) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the ring backbone. When the heteroaryl is a ring system, every ring in the system is aromatic. The heteroaryl group may have 5-18 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heteroaryl” where no numerical range is designated. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as “5-7 membered heteroaryl,” “5-10 membered heteroaryl,” or similar designations. Examples of heteroaryl rings include, but are not limited to, furyl, thienyl, phthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinlinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl.
- A “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. Examples include but are not limited to 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl. In some cases, the alkylene group is a lower alkylene group (i.e., a C1-4 alkylene group).
- As used herein, “carbocyclyl” means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6 carbocyclyl” or similar designations. Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.
- A “(carbocyclyl)alkyl” is a carbocyclyl group connected, as a substituent, via an alkylene group, such as “C4-10 (carbocyclyl)alkyl” and the like, including but not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.
- As used herein, “cycloalkyl” means a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
- As used herein, “cycloalkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.
- As used herein, “heterocyclyl” means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.
- A “(heterocyclyl)alkyl” is a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.
- As used herein, “acyl” refers to —C(═O)R, wherein R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.
- An “O-carboxy” group refers to a “—OC(═O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- A “C-carboxy” group refers to a “—C(═O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., —C(═O)OH).
- A “cyano” group refers to a “—CN” group.
- A “cyanato” group refers to an “—OCN” group.
- An “isocyanato” group refers to a “—NCO” group.
- A “thiocyanato” group refers to a “—SCN” group.
- An “isothiocyanato” group refers to an “—NCS” group.
- A “sulfinyl” group refers to an “—S(═O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- A “sulfonyl” group refers to an “—SO2R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “S-sulfonamido” group refers to a “—SO2NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “N-sulfonamido” group refers to a “—N(RA)SO2RB” group in which RA and Rb are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “O-carbamyl” group refers to a “—OC(═O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “N-carbamyl” group refers to an “—N(RA)OC(═O)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “O-thiocarbamyl” group refers to a “—OC(═S)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, a C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “N-thiocarbamyl” group refers to an “—N(RA)OC(═S)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- A “C-amido” group refers to a “—C(═O)NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “N-amido” group refers to a “—N(RA)C(═O)RB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “amino” group refers to a “—NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.
- An “aminoalkyl” group refers to an amino group connected via an alkylene group.
- An “alkoxyalkyl” group refers to an alkoxy group connected via an alkylene group, such as a “C2-8 alkoxyalkyl” and the like.
- As used herein, a substituted group is derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” it is meant that the group is substituted with one or more substitutents independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., —CF3), halo(C1-C6)alkoxy (e.g., —OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (═O). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.
- In some embodiments, substituted group(s) is (are) substituted with one or more substituent(s) individually and independently selected from C1-C4 alkyl, amino, hydroxy, and halogen.
- It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as —CH2—, —CH2CH2—, —CH2CH(CH3)CH2—, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”
- As used herein, “alkylene” means a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogen that is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as “C1-4 alkylene” or similar designations. By way of example only, “C1-4 alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-1,1-diyl, propylene, propan-1,1-diyl, propan-2,2-diyl, 1-methyl-ethylene, butylene, butan-1,1-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.
- As used herein, “alkenylene” means a straight or branched chain di-radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as “C2-4 alkenylene” or similar designations. By way of example only, “C2-4 alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-en-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, buten-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-en-1,1-diyl, but-3-en-1,1-diyl, 1-methyl-prop-2-en-1,1-diyl, 2-methyl-prop-2-en-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.
- The compounds described herein, including but not limited to the compounds of formula (Ia), (Ib), (IIa), (IIb), (III), (IVa), (IVb), (Va), (Vb), (VI), the first reaction intermediate, or the second reaction intermediate, should be understood to also include the ionic form of the compound when in solution.
- Salts described herein include but are not limited to salts of such compound with an organic or inorganic acid or with an organic or inorganic base. In many cases, the compounds herein are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Many such salts are known in the art, as described in WO 87/05297, Johnston et al., published Sep. 11, 1987 (incorporated by reference herein in its entirety).
- One aspect of the present technology relates to a process for production of a compound of Formula (Ia) or (Ib) or salt thereof,
-
- the process comprising:
- providing a first continuous flow of a lithium amide;
- providing a continuous flow of a compound of Formula (IIa) or (IIb) or salt thereof;
-
- combining the first continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb) or salt thereof at a first continuous flow conduit at a first temperature to yield a first reaction intermediate;
- transitioning the first reaction intermediate to a second temperature to yield a second reaction intermediate; and
- combining the second reaction intermediate and a compound of Formula (III) or salt thereof downstream of the second continuous flow conduit to yield the compound of Formula (Ia) or (Ib) or salt thereof
-
A-O—C(O)—(CH2)nG (III). - In some embodiments, transitioning the first reaction intermediate to a second temperature to yield a second reaction intermediate comprises delivering the first reaction intermediate to a second continuous flow conduit at the second temperature to yield the second reaction intermediate.
- In some embodiments, the second reaction intermediate is collected in a vessel wherein the vessel does not have a continuous outflow. In some embodiments, the second reaction intermediate is collected in a vessel wherein the vessel is a continuous outflow or includes at least one continuous flow.
- In some embodiments, the lithium amide solution can be a continuous flow of the lithium amide in one or more suitable organic solvents. In some embodiments, the first continuous flow of the lithium amide is a continuous flow of the lithium amide in tetrahydrofuran, heptane, hexane, cyclohexane, toluene, or any combinations thereof. In some embodiments, the first continuous flow of the lithium amide is a continuous flow of the lithium amide in tetrahydrofuran.
- In some embodiments, the providing a first continuous flow of a lithium amide further comprises
-
- providing a continuous flow of tetrahydrofuran;
- providing a second continuous flow of the lithium amide; and
- combining the continuous flow of tetrahydrofuran and the second continuous flow of the lithium amide before the first continuous flow conduit to form the first continuous flow of the lithium amide.
- The second continuous flow of the lithium amide can be in one or more suitable solvents. In some embodiments, the second continuous flow of the lithium amide is in tetrahydrofuran.
- In some embodiments, a lithium amide can be a dipolar compound represented by the general formula RR′NLi or LiN(SiR3)(SiR′3), wherein R and R′ are each independently selected from, optionally substituted C1-10 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6alkylene-C3-7carbocyclyl, optionally substituted C1-6alkylene-5-10 membered heterocyclyl, optionally substituted C1-6alkylene-C6-10aryl, or optionally substituted C1-6alkylene-5-10 membered heteroaryl. In some embodiments, the lithium amide is lithium bis(trimethylsilyl)amide. In some embodiments, the lithium amide is lithium diisopropylamide, lithium diethylamide, lithium pyrrolidide, lithium piperidide, or lithium 2,2,6,6,-tetramethylpiperidide.
- The continuous flow of the compound of Formula (IIa) or (IIb) can be a continuous flow of the compound of Formula (IIa) or (IIb) in one or more suitable organic solvents. In some embodiments, the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in tetrahydrofuran. In some embodiments, the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in heptane. In some embodiments, the continuous flow of the compound of Formula (IIa) or (IIb) is a continuous flow of the compound of Formula (IIa) or (IIb) in heptane and tetrahydrofuran.
- In some embodiments, a solution of the compound of Formula (IIa) or (IIb) stored in a vessel may be combined with additional organic solvent (e.g., tetrahydrofuran) to reach a more preferred concentration before the solution flows out of the vessel. In some embodiments, a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 20% to 60% by weight of the compound of Formula (IIa) or (IIb). In some embodiments, a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 25% to 55% by weight of the compound of Formula (IIa) or (IIb). In some embodiments, a solution of the compound of Formula (IIa) or (IIb) flowing out of the vessel can have a concentration of about 25% to 35% by weight of the compound of Formula (IIa) or (IIb).
- The vessel storing a solution of the compound of Formula (IIa) or (IIb) can be pressurized to generate a preferred flow rate for the compound of Formula (IIa) or (IIb). In some embodiments, the flow rate of the compound of Formula (IIa) or (IIb) is in the range of about 0.17 kg/h to about 0.23 kg/h. In some embodiments, the flow rate is in the range of about 0.1 kg/h to about 0.4 kg/h. In some embodiments, the flow rate is in the range of about 0.15 kg/h to about 0.25 kg/h. In some embodiments, the flow rate is about 0.19 kg/h.
- In some embodiments, the first reaction intermediate comprises a compound having the structure of formula (IVa) or (IVb) or salt thereof
- In some embodiments, the first reaction intermediate comprises a compound having the structure of formula (IVa). In some embodiments, the first reaction intermediate comprises
- or salt thereof.
- In some embodiments, the second reaction intermediate comprises a compound having the structure of formula (Va) or (Vb) or salt thereof
- In some embodiments, the second reaction intermediate comprises a compound having the structure of formula (Va). In some embodiments, the second reaction intermediate comprises
- or salt thereof.
- The process described herein can further include preparing the reagents or solvents used in the process under an inert atmosphere. In some embodiments, the process described herein can further include preparing the lithium amide, the compound of formula (IIa) or (IIb), and the tetrahydrofuran under a nitrogen or argon atmosphere. In some embodiments, the process can include preparing the compound of formula (III) under an inert atmosphere.
- The reagents and solvents used in this process can be substantially free of water. In some embodiments, the lithium amide, the compound of formula (IIa) or (IIb), the trimethylsilyl chloride, and the tetrahydrofuran used in the process are substantially free of water.
- The process described herein can further include combining trimethylsilyl chloride to the compound of formula (IIa) or (IIb) prior to providing a continuous flow of a compound of formula (IIa) or (IIb). In some embodiments, the continuous flow of the compound of formula (IIa) or (IIb) include trimethylsilyl chloride. In some embodiments, the continuous flow of the compound of formula (IIa) or (IIb) does not include trimethylsilyl chloride.
- The process described herein can further include preparing a compound of formula (III) in a vessel downstream of the second continuous flow conduit. In some embodiments, preparing the compound of formula (III) includes combining a compound of formula (VI) G-(CH2)n—COOH (VI), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl), and Hydroxybenzotriazole (HOBt) in a vessel. In some embodiments, preparing the compound of formula (III) is performed at a temperature in the range of about −10° C. to 10° C. In some embodiments, preparing the compound of formula (III) is performed at 0° C.
- The process can further include pre-cooling the lithium amide to a temperature in the range of about −50° C. to about 0° C. The pre-cooling process can include one or more stages of gradually lowering the temperature. For example, the pre-cooling described herein can include a first stage of lowering the temperature and a second stage of further lowering the temperature. In some embodiments, the process described herein can include pre-cooling the lithium amide to a temperature of about −90° C., −80° C., −75° C., −70° C., −65° C., −60° C., −50° C., −40° C., −30° C., −25° C., −10° C., or −5° C. prior to delivering the lithium amide to the first continuous flow conduit. In some embodiments, the process described herein can further include a first stage of pre-cooling the lithium amide to a temperature in the range of about −100° C. to 0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., −40° C. to −10° C., −30° C. to 0° C., −20° C. to 0° C., or −15° C. to 0° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran. In some embodiments, the process described herein can further include a first stage of pre-cooling the lithium amide to a temperature in the range of about −30° C. to 0° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran.
- In an embodiment wherein a continuous flow of tetrahydrofuran is provided separately from the lithium amide solution, the process described herein can further comprise pre-cooling the tetrahydrofuran. In some embodiments, the tetrahydrofuran can be pre-cooled to a temperature in the range of about −80° C. to −20° C. prior to being combined with the separate continuous flow of the lithium amide. In some embodiments, the tetrahydrofuran can be pre-cooled to a temperature in the range of about −80° C. to −65° C. prior to being combined with the separate continuous flow of the lithium amide. In some embodiments, the tetrahydrofuran can be pre-cooled to a temperature of about −80° C., −75° C., −70° C., −65° C., or −60° C. prior to the being combined with the continuous flow of tetrahydrofuran and the second continuous flow of the lithium amide. In some embodiments, the tetrahydrofuran can be pre-cooled to a temperature of in the range of about −100° C. to −0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., or −40° C. to −10° C. prior to the being combined with the continuous flow of tetrahydrofuran and the second continuous flow of the lithium amide.
- In such an embodiment, the process described herein can further comprise pre-cooling the separate continuous flow of the lithium amide. In such an embodiment, the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about −80° C. to −10° C. prior to being combined with the continuous flow of tetrahydrofuran. In some embodiments, the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about −80° C. to −10° C. prior to being combined with the continuous flow of tetrahydrofuran. In some embodiments, the separate continuous flow of the lithium amide can be pre-cooled to a temperature of about −80° C., −75° C., −70° C., −60° C., 60° C., −55° C., −50° C., −40° C., −30° C., −20° C., −10° C., or −5° C. prior to being combined with the continuous flow of tetrahydrofuran. In some embodiments, the separate continuous flow of the lithium amide can be pre-cooled to a temperature in the range of about −100° C. to −0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., or −40° C. to −10° C. prior to being combined with the continuous flow of tetrahydrofuran.
- The process can further include pre-cooling the tetrahydrofuran to a temperature in the range of about −100° C. to about 0° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran. In some embodiments, the process described herein can further include pre-cooling the tetrahydrofuran to a temperature of about −90° C., −80° C., −75° C., −70° C., −65° C., −60° C., −55° C., −50° C., −40° C., −30° C., −20° C., −10° C., or −5° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran. In some embodiments, the process described herein can further include pre-cooling the tetrahydrofuran to a temperature in the range of about −100° C. to −0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., or −40° C. to −10° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran. In some embodiments, the process described herein can further include pre-cooling the tetrahydrofuran to about −30° C. prior to the combining of the first continuous flow of the lithium amide and the continuous flow of tetrahydrofuran.
- The process can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature suitable for the lithium amide addition reaction. In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about −100° C. to about 0° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb). In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature of about −90° C., −80° C., −75° C., −70° C., −65° C., −60° C., −55° C., −50° C., −40° C., −30° C., −20° C., −10° C., or −5° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb). In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature of about −30° C. prior to the combining of the continuous flow of the lithium amide and the continuous flow of the compound of Formula (IIa) or (IIb). In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about −50° C. to 0° C. or −30° C. to 0° C. prior to the combining of the continuous flow of the first reaction intermediate and the continuous flow of the compound of Formula (IIa) or (IIb). In some embodiments, the process described herein can further include pre-cooling the compound of Formula (IIa) or (IIb) to a temperature in the range of about −100° C. to 0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., −40° C. to −10° C., −30° C. to 0° C., −20° C. to 0° C., or −15° C. to 0° C. prior to the combining of the continuous flow of the first reaction intermediate and the continuous flow of the compound of Formula (IIa) or (IIb).
- The process described herein can further include maintaining the first continuous flow conduit at a temperature in the range of about −100° C. to about 0° C. during the process. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about −85° C., −80° C., −75° C., −70° C., −65° C., 60° C., −55° C., −50° C., −40° C., −30° C., −20° C., −10° C., or −5° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about −50° C., −40° C., −30° C., −20° C., or −10° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about −30° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of about −35° C. In some embodiments, the process described herein can further include maintaining the first continuous flow conduit at a temperature of in the range of about −100° C. to −0° C., −90° C. to −10° C., −80° C. to −10° C., −80° C. to −20° C., −70° C. to −20° C., −70° C. to −10° C., −60° C. to −20° C., −60° C. to −10° C., −50° C. to −30° C., −50° C. to −20° C., −50° C. to −10° C., −40° C. to −20° C., −40° C. to −10° C., or −40° C. to −30° C.
- The process described herein can further include maintaining the second continuous flow conduit at a temperature in the range of about −30° C. to about 40° C., about −20° C. to about 30° C., about 0° C. to about 45° C., or about 0° C. to about 25° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature of about −30° C., −20° C., −10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 40° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature of about −10° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature of about 25° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature no greater than 40° C. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a room temperature. In some embodiments, the process described herein can further include maintaining the second continuous flow conduit at a temperature in the range of about −40° C. to 40° C., −30° C. to 30° C., −20° C. to 40° C., −20° C. to 35° C., −20° C. to 30° C., −20° C. to 25° C., −20° C. to 20° C., −10° C. to 40° C., −10° C. to 35° C., −10° C. to 30° C., −10° C. to 25° C., −5° C. to 40° C., −5° C. to 35° C., −5° C. to 30° C., −5° C. to 25° C., −5° C. to 20° C., −5° C. to 15° C., 0° C. to 40° C., 0° C. to 35° C., 0° C. to 30° C., 0° C. to 25° C., 0° C. to 20° C., 0° C. to 15° C., 5° C. to 40° C., 5° C. to 35° C., 5° C. to 30° C., 5° C. to 25° C., 5° C. to 20° C., 5° C. to 15° C., 10° C. to 40° C., 10° C. to 35° C., 10° C. to 30° C., 10° C. to 25° C., 10° C. to 20° C., or 10° C. to 15° C.
- The process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature in the range of about −30° C. to about 30° C., about −20° C. to about 20° C., about −10° C. to about 20° C., about −5° C. to about 20° C., about −10° C. to about 10° C., about −5° C. to about 5° C., or about 0° C. to about 5° C. In some embodiments, the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about −5° C. to about 10° C. In some embodiments, the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about −30° C., −20° C., −10° C., −5° C., 0° C., 5° C., 10° C., 15° C., 20° C., 25° C., 30° C., or 40° C. In some embodiments, the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of 0° C. In some embodiments, the process described herein can further include maintaining the vessel that is downstream of the second continuous flow conduit at a temperature of about −40° C. to 40° C., −30° C. to 30° C., −20° C. to 40° C., −20° C. to 35° C., −20° C. to 30° C., −20° C. to 25° C., −20° C. to 20° C., −20° C. to 15° C., −20° C. to 5° C., −20° C. to 0° C., −20° C. to −10° C., −10° C. to 40° C., −10° C. to 35° C., −10° C. to 30° C., −10° C. to 25° C., −10° C. to 20° C., −10° C. to 15° C., −10° C. to 5° C., −10° C. to 0° C., −10° C. to −5° C., −5° C. to 40° C., −5° C. to 35° C., −5° C. to 30° C., −5° C. to 25° C., −5° C. to 20° C., −5° C. to 15° C., −5° C. to 5° C., or −5° C. to 0° C. When the vessel is maintained at the selected temperature or temperature range described above, the reaction mixture in the vessel can be stirred for at least about 5 min, 20 min, 0.5 h, 1 h, 2 h, 3 h, 5 h, or 12 h. In some embodiments, the reaction mixture in the vessel can be kept stirring at the selected temperature or temperature range for about 5 min-1 h, 5 min-3 h, or 5 min-12 h.
- In some embodiments, in addition to the step of maintaining the vessel that is downstream of the second continuous flow conduit at a low temperature (e.g, about −30° C. to about 30° C., about −20° C. to about 20° C., about −10° C. to about 20° C., about −5° C. to about 20° C., about −10° C. to about 10° C., about −5° C. to about 5° C., or about 0° C. to about 5° C.), the process described herein also includes a step of warning up the vessel to a room temperature (e.g., 18° C. to 30° C. or 18° C. to 24° C.) and stirring the reaction mixture in the vessel for at least about 5 min, 20 min, 0.5 h, 1 h, 3 h, 5 h, or 12 h.
- The flow time in the continuous flow conduit can vary depending on the flow rate and the length of the continuous flow conduit. In some embodiments, a flow time from in the first continuous flow conduit is about 20 s-200 s, about 40 s-about 120 s, about 50 s-100 s, or about 60 s-80 s. In some embodiments, a flow time in the first continuous flow conduit is about 20 s, 30 s, 40 s, 50 s, 60 s, 70 s, 72 s, 75 s, 80 s, 90 s, 100 s, 110 s, 120 s, 130 s, 140 s, 150 s, 160 s, 170 s, 180 s, 190 s, or 200 s. In some embodiments, a flow time in the first continuous flow conduit is about 72 seconds. In some embodiments, a flow time in the first continuous flow conduit is in the range of about 10 s-200 s, 20 s-180 s, 20 s-160 s, 20 s-150 s, 20 s-120 s, 20 s-100 s, 20 s-80 s, 30 s-200 s, 30 s-180 s, 30 s-150 s, 30 s-120 s, 30 s-100 s, 30 s-80 s, 40 s-200 s, 40 s-180 s, 40 s-160 s, 40 s-150 s, 40 s-120 s, 40 s-100 s, 40 s-80 s, 50 s-200 s, 50 s-180 s, 50 s-160 s, 50 s-150 s, 50 s-120 s, 50 s-100 s, 50 s-80 s, 60 s-200 s, 60 s-180 s, 60 s-160 s, 60 s-150 s, 60 s-120 s, 60 s-100 s, 60 s-80 s, 70 s-200 s, 70 s-180 s, 70 s-150 s, 70 s-120 s, 70 s-100 s, 70 s-80 s, or 80 s-100 s.
- In some embodiments, a flow time in the second continuous flow conduit is about 5 min to about 30 min, about 10 min to about 25 min, about 12 min to about 20 min, or about 14 min to about 15 min. In some embodiments, a flow time in the second continuous flow conduit is about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 min. In some embodiments, a flow time in the second continuous flow conduit is about 14 min. In some embodiments, a flow time in the second continuous flow conduit is about 15 min. In some embodiments, a flow time in the second continuous flow conduit is in the range of about 1 min-50 min, 1 min-40 min, 1 min-30 min, 1 min-25 min, 1 min-20 min, 1 min-18 min, 1 min-15 min, 3 min-50 min, 3 min-40 min, 3 min-30 min, 3 min-25 min, 3 min-20 min, 3 min-18 min, 3 min-15 min, 5 mm-50 min, 5 min-40 min, 5 min-30 min, 5 min-25 min, 5 min-20 min, 5 min-18 min, 5 min-15 min, 5 min-10 min, 8 min-50 min, 8 min-40 min, 8 min-30 min, 8 min-25 min, 8 min-20 min, 8 min-18 min, 8 min-15 min, 8 min-10 min, 10 min-50 min, 10 min-40 min, 10 min-30 min, 10 min-25 min, 10 min-20 min, 10 min-18 min, 10 min-15 min, or 10 min-12 min.
- In some embodiments, the reaction mixture of the second reaction intermediate and the compound of Formula (III), which are combined downstream of the second continuous flow conduit, are suspended in a vessel and stirred for about 0.5 h-7 h, 1 h-6 h, or about 2 h-5 h. In some embodiments, the mixture of the second reaction intermediate and the compound of Formula (III) are suspended in a vessel and stirred for about 2 h-5 h.
- In some embodiments where lithium amide is in a solvent (e.g., tetrahydrofuran), the concentration of the lithium amide prior to flowing into the first continuous flow conduit can be about 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is about 25%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is lower than 25%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 15% to about 45%, about 15% to 30%, about 15% to about 25%, about 20% to 40%, or about 22% to about 27%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 25% to about 50%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 20% to about 60%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 1%-100%, 5%-90%, 10%-80%, 10%-70%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-20%, 15%-80%, 15%-70%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-20%, 20%-80%, 20%-70%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, or 20%-25%.
- The lithium amide solution can be stored in a vessel and the vessel can be pressurized to generate a preferred flow rate for the lithium amide solution flowing out of the vessel. In some embodiments, the flow rate for the lithium amide solution is in the range of about 0.09 kg/h to about 0.13 kg/h. In some embodiments, the flow rate is in the range of about 0.05 kg/h to about 0.2 kg/h. In some embodiments, the flow rate is in the range of about 0.1 kg/h to about 0.15 kg/h.
- For embodiments wherein lithium amide is combined with additional tetrahydrofuran prior to flowing into the first continuous flow conduit, the concentration of the lithium amide in tetrahydrofuran is about 10%, 15%, 20%, 25%, 30%, 35%, or 40%. In some embodiments, the concentration of the lithium amide in tetrahydrofuran is about 25%. In some embodiments, the concentration of the lithium amide in tetrahydrofuran is about 15%-30%, about 20%-40%, or about 22% to about 27%. In some embodiments, the concentration of the lithium amide in tetrahydrofuran is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, or 20%-25%.
- In embodiments where the compound of (IIa) or (IIb) is in a solvent (e.g., tetrahydrofuran), the concentration of the compound of (IIa) or (IIb) prior to flowing into the first continuous flow conduit or in some embodiments is about 10%, 15%, 20%, 25%, 27%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%. In embodiments where lithium amide is in a solvent (e.g., tetrahydrofuran), the concentration of the lithium amide prior to flowing into the first continuous flow conduit or in some embodiments is about 27%. In embodiments where lithium amide is in a solvent (e.g., tetrahydrofuran), the concentration of the lithium amide prior to flowing into the first continuous flow conduit or in some embodiments is about 45%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 15% to about 75%, about 30% to 50%, about 25% to 50%, or about 40% to about 50%. In some embodiments, the concentration of the lithium amide prior to flowing into the first continuous flow conduit is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- In some embodiments, a small amount of trimethylsilyl chloride is added to the solution containing the compound of (IIa) or (IIb) prior to combining the solution with the lithium amide. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is about 0.01, 0.02, 0.03, 0.04, 0.05, or 0.06. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is about 0.03. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is in the range of about 0.01 to 0.1, about 0.02 to about 0.05, or about 0.02 to about 0.04. In some embodiments, the molar ratio of trimethylsilyl chloride to the compound of formula (IIa) or (IIb) is in the range of about 0.001-1, 0.001-0.5, 0.001-0.1, 0.001-0.05, 0.005-1, 0.005-0.5, 0.005-0.1, 0.005-0.05, 0.01-1, 0.01-0.5, 0.01-0.1, 0.01-0.05, 0.02-1, 0.02-0.5, 0.02-0.1, 0.02-0.04, 0.02-0.05, 0.03-1, 0.03-0.5, 0.03-0.1, or 0.03-0.05. In some embodiments, no trimethylsilyl chloride is added to the solution containing the compound of (IIa) or (IIb) prior to combining the solution with the lithium amide.
- The molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) can vary depending on the reaction temperature, the reaction solvent, and other reaction conditions in the continuous flow conduit. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is in the range of about 10 to 0.1, about 5 to about 0.5, about 2 to about 0.8, or about 1.5 to about 1. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is about 1.1. In some embodiments, the molar ratio of the lithium amide to the compound of formula (IIa) or (IIb) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, or 0.75-0.8.
- In embodiments where a continuous flow of the lithium amide is established prior to combination with tetrahydrofuran, the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran can vary depending on the reaction conditions. In some embodiments, the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran is about 25%. In some embodiments, the concentration of the lithium amide in the continuous flow prior to combination with the tetrahydrofuran is in the range of about 24% to about 26%. In some embodiments, the concentration of the lithium amide in the continuous flow prior to being combined with the tetrahydrofuran is in the range of about 15% to about 35%. In some embodiments, the concentration of the lithium amide in the continuous flow prior to combination with the tetrahydrofuran is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- The concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit can vary depending on the reaction conditions. In some embodiments, the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is about 5%, 10%, 20%, 30%, 40%, 45%, 50%, or 60%. In some embodiments, the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is in the range of about 1% to about 80%, bout 10% to about 60%, or about 15% to about 50%. In some embodiments, the concentration of the lithium amide in the continuous flow after being combined with the tetrahydrofuran but prior to flowing into the first continuous flow conduit is in the range of about 1%-80%, 1%-60%, 1%-50%, 1%-40%, 1%-30%, 1%-27%, 1%-25%, 5%-80%, 5%-60%, 5%-50%, 5%-40%, 5%-27%, 5%-30%, 5%-25%, 10%-80%, 10%-60%, 10%-50%, 10%-40%, 10%-30%, 10%-27%, 10%-25%, 15%-80%, 15%-60%, 15%-50%, 15%-40%, 15%-30%, 15%-27%, 15%-25%, 20%-80%, 20%-60%, 20%-50%, 20%-40%, 20%-30%, 20%-27%, or 20%-25%.
- The molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) can vary depending on the reaction temperature and other reaction conditions in the continuous flow conduit. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) is about 0.5-3, about 0.8-2, or about 1-1.5. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) is about 1-1.5. In some embodiments, the molar ratio of Lewis acid to the compound of Formula (IIa) or (IIb) is higher than about 1. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is about 1.3. In some embodiments, the molar ratio of the compound of formula (III) to the compound of Formula (IIa) or (IIb) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- The concentration of HOBt in the vessel prior to reacting with the compound of formula (VI) may vary depending on the reaction condition. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 0.5-3, about 0.8-2, or about 0.9-1.1. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 0.8-1.2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is higher than about 1. In some embodiments, the molar ratio of the HOBt to the compound of formula (IV) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 1.3. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- The concentration of EDC.HCl in the vessel prior to reacting with the compound of formula (VI) may vary depending on the reaction condition. In some embodiments, the molar ratio of EDC.HCl to the compound of formula (VI) is about 0.5-5, about 0.8-2, or about 0.9-1.5. In some embodiments, the molar ratio of EDC.HCl to the compound of formula (VI) is about 1-1.5. In some embodiments, the molar ratio of EDC.HCl to the compound of formula (VI) is higher than about 1. In some embodiments, the molar ratio of the EDC.HCl to the compound of formula (VI) is about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is about 1.6:1.3. In some embodiments, the molar ratio of HOBt to the compound of formula (VI) is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.8, 1-5, 1-4, 1-3, 1-2, 1-1.5, 1-1.3, 1-1.25, 1.15-1.5, or 1.15-1.25.
- In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 1-1.3 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 0.8-1.6 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 1.1-1.3 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of the compound of formula (VI) added into the vessel is about 1.2 molar equivalent of the compound of formula (IIa) or (IIb).
- In some embodiments, the amount of HOBt added into the vessel is about 1-1.5 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 0.8-1.8 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 1.2-1.4 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of HOBt added into the vessel is about 1.3 molar equivalent of the compound of formula (IIa) or (IIb).
- In some embodiments, the amount of EDC.HCl added into the vessel is about 1-2 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 0.5-2.5 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 1.4-1.8 molar equivalent of the compound of formula (IIa) or (IIb). In some embodiments, the amount of EDC.HCl added into the vessel is about 1.6 molar equivalent of the compound of formula (IIa) or (IIb).
- The flow rate of the compound of formula (IIa) or (IIb) in the first continuous flow conduit may vary depending on the reaction conditions. The process described herein can include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate of about 0.05 mmol/min, 0.1 mmol/min, 0.12 mmol/min, 0.14 mmol/min, 0.16 mmol/min, 0.17 mmol/min, or 0.18 mmol/min. In some embodiments, the process described herein can further include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate no greater than 0.5 mmol/min, 1 mmol/1, 1.5 mmol/min, 2 mmol/min, 2.5 mmol/min, 3 mmol/min, 3.5 mmol/min, 4 mmol/min, 4.5 mmol/min, or 5 mmol/min. In some embodiments, the process described herein can further include flowing the compound of formula (IIa) or (IIb) into the first continuous flow conduit at a flow rate of about 0.1 mmol/min to about 5.0 mmol/min, or about 1 mmol/min to about 3 mmol/min. In some embodiments, the compound of formula (IIa) or (IIb) flow rate is about 0.05 mmol/min to about 1.2 mmol/min, about 0.05 mmol/min to about 1.0 mmol/min, or 0.1 mmol/min to about 0.5 mmol/min. In some embodiments, the compound of formula (IIa) or (IIb) flow rate is about 0.17 mmol/min.
- The flow rate of the lithium amide in the first continuous flow conduit may vary depending on the reaction conditions. The process described herein can include flowing lithium amide into the first continuous flow conduit at a flow rate of about 0.2 mmol/min, 0.4 mmol/min, 0.6 mmol/min, 0.8 mmol/min, 1 mmol/min, 1.2 mmol/min, or 1.5 mmol/min. The process described herein can further include flowing the lithium amide into the first continuous flow conduit at a flow rate of about 0.2 mmol/min to about 5 mmol/min, about 0.5 mmol/min to about 2 mmol/min, or about 0.7 to about 0.9 mmol/min. In some embodiments, the lithium amide flow rate is about 0.87 mmol/min. In some embodiments, the lithium amide flow rate is about 0.9 mmol/min. In some embodiments, the lithium amide flow rate is in the range of about 0.1-5, 0.1-4, 0.1-3, 0.1-2, 0.1-1.5, 0.1-1.25, 0.1-1, 0.1-0.9, 0.1-0.8, 0.1-0.5, 0.5-5, 0.5-4, 0.5-3, 0.5-2, 0.5-1.5, 0.5-1.25, 0.5-1, 0.5-0.9, 0.5-0.8, 0.1-5, 0.75-4, 0.75-3, 0.75-2, 0.75-1.5, 0.75-1.25, 0.75-1, 0.75-0.9, or 0.75-0.8 mmol/min. In some embodiments, the process described herein can further include flowing the lithium amide into the first continuous flow conduit at a flow rate no greater than 0.5 mmol/min, 1 mmol/l, 1.5 mmol/min, 2 mmol/min, 2.5 mmol/min, 3 mmol/min, 3.5 mmol/min, 4 mmol/min, 4.5 mmol/min, or 5 mmol/min.
- In some embodiments, the reaction between of the second reaction intermediate with compound of formula (III) is not performed in a continuous flow conduit. In some embodiments, the reaction between of the second reaction intermediate with compound of formula (III) is performed in a flask or other reaction vessel that does not involve continuous flowing.
- The process described herein can also include one or more steps known by those skilled in the art to be suitable for separating and purifying the compound of formula (Ia) or (Ib). The separation and/or purification can include extraction, distillation, chromatography, crystallization, and other suitable purifying methods known by those skilled in the art. For example, the separation and/or purification can include multiple extraction steps using the same or different solvents in each extraction step, and one or more distillation steps can be used following the extraction to further purify the final product. In some embodiments, the purification includes a crystallization step.
- The process described herein can further include one or more steps of preparing stock solution of the various reagents. In some embodiments, the process described herein can further include combining lithium amide and tetrahydrofuran to prepare an lithium amide stock solution for the first continuous flow of the lithium amide. In an embodiment wherein the continuous flow of tetrahydrofuran and the continuous flow of the lithium amide are provided separately. In some embodiments, the process described herein can further include combining the compound of formula (IIa) or (IIb) and tetrahydrofuran to provide the compound of formula (IIa) or (IIb) stock solution for the continuous flow of the compound of formula (IIa) or (IIb). In some embodiments, the process described herein can further include combining the compound of formula (IIa) or (IIb), tetrahydrofuran, and trimethylsilyl chloride to provide the compound of formula (IIa) or (IIb) stock solution for the continuous flow of the compound of formula (IIa) or (IIb).
- The process described herein can also include pressurizing the vessel containing the stock solutions. In some embodiments, the process described herein includes pressurizing the first or the fifth vessel comprising the lithium amide stock solution. In some embodiments, the process described herein includes pressurizing the second or sixth vessel comprising the compound of formula (IIa) or (IIb) stock solution. In an embodiment wherein the continuous flow of tetrahydrofuran and the continuous flow of the lithium amide are provided separately, the process described herein can further include preparing a stock solution of the lithium amide in tetrahydrofuran and pressurizing a vessel comprising the lithium amide in tetrahydrofuran stock solution. In such an embodiment, the process described herein can further include preparing a stock solution of tetrahydrofuran and pressurizing a vessel comprising the tetrahydrofuran stock solution.
- In some embodiments, the process includes producing the compound of Formula Ia. In some embodiments, for the compound of Formula (Ia), M is —CH═CH— and n is 1. In some embodiments, for the compound of Formula (Ia), M is —CH2— and Q is —CH2— or —CH2—CH2—.
- In some embodiments, the process includes producing the compound of Formula (Ib) or salt thereof.
-
- R1 can be any suitable carboxylic acid protection group, such as ester forming groups or silyl groups. In some embodiments, R1 is tert-butyl (t-Bu). In some embodiments, R1 is selected from methyl, ethyl, propyl, isopropyl, t-butyl, t-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, β-methylsulfonylethyl, methylthiomethyl, trityl, β,β,β-trichloroethyl, β-iodoethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, p-nitrobenzoylmethyl, p-mesylbenzoylmethyl, phthalimidomethyl, propionyloxymethyl, 1,1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl, 3,5-di-t-butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonyl-methyl, phenylthiomethyl, dimethylaminomethyl, pyridine-1-oxide-2-methyl, methylsulfinylmethyl, bis(p-methoxyphenyl)methyl, or 2-cyano-1,1-dimethylethyl. Some commonly used carboxylic acid protection groups are t-butyl, benzyl, β,β,β-trichloroethyl, p-nitrobenzyl, p-methoxybenzyl, trimethylsilyl, dimethyl-t-butylsilyl, phenacetyl or acetonyl.
- R2 can be any suitable hydroxyl protection group. In some embodiments, R2 is tert-butyldimethylsilyl (TBDMS). In some embodiments, R2 is selected from benzyl, benzoyl, 2,6-dichlorobenzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, mesylate, tosylate, dimethoxytrityl (DMT), 9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX), acetyl, benzyl, or 4,4′-dimethoxytrityl.
- In some embodiments, the compound of Formula Ia is
- or salt thereof.
- In some embodiments, the compound of Formula (IIa) is
- or salt thereof.
- The process described herein can further include performing the reaction of the compound of formula (III) and the second reaction intermediate under a nitrogen or argon atmosphere.
- In some embodiments, the process described herein can further include analyzing a reaction flow sample taken after the first continuous flow conduit but before the second continuous flow conduit. In some embodiments, the process described herein can further include analyzing a reaction flow sample taken after the second continuous flow conduit but before the vessel that contains the compound of formula (III).
- The analysis of reaction samples can be performed using any suitable known analytic methods. In some embodiments, the process described herein includes analyzing the reaction sample using a chromatography. In some embodiments, the process described herein includes analyzing the reaction sample using a HPLC.
- The process described herein can be used for production of the compound of formula (Ia) or (Ib) on a plant scale or pilot plant scale. The process described herein can be used to produce over about 10 kg, 20 kg, 50 kg, 80 kg, 100 kg, 150 kg, 180 kg, or 200 kg of the compound of formula (Ia) or (Ib) per day.
- In some embodiments, an additional flow for THE can be introduced to have better control over lithium amide concentration and stoichiometry and help enhance process robustness by prevention blocking of the LT tube reactor by precipitation of the lithium amide.
- In some embodiments, compound (IIa) or (IIb) concentration can be reduced or adjusted based on the lithium amide concentration in the flow after the dilution using an additional flow of THF. The dilution using an additional flow of THE can help ensure higher yield and better conversion of raw materials comparative to other known process.
- In some embodiments, the continuous flow conduit, including the first and the second continuous flow conduit, can be lengthened so increase the residence time to an extent that additional stirring in collection vessel at ambient temperature is no longer required to achieve full conversion of starting material compound of formula (IIa) or (IIb). This can help simply the process, shorten the production time, and save the use of any stirring vessel.
- In some embodiments, full conversion of the starting material compound of formula (IIa) or (IIb) can be achieved in the process and the second reaction intermediate (e.g., compound 2d) can be directly delivered to the solution containing the active ester compound of formula (III).
- In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, 0.25% or 0.1% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 5% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 1.4% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 1% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is less than about 0.9% in the final product. In some embodiments, the amount of impurity compound resulted from lithium amide side reaction (e.g. compound S1 or S2) is in the range of about 0.1% to about 10%, about 0.1% to about 5%, about 0.15 to about 1.0% in the final product.
- In some embodiments, the amount of the diastereomer of the compound of formula (Ia) or (Ib) is less than about 1% in the final product. In some embodiments, the amount of the diastereomer of the compound of formula (Ia) or (Ib) is less than about 0.9%, 0.8%, 0.6%, 0.4%, 0.2%, or 0.1% in the final product. In some embodiments, the amount of the diastereomer of the compound of formula (Ia) or (Ib) is in the range of about 0.1% to about 10%, about 0.1% to about 5%, about 0.15 to about 1.0% in the final product.
- In some embodiments, the amount of total impurities is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1%, 0.5%, 0.25% or 0.1% in the final product. In some embodiments, the amount of total impurities is less than about 8% in the final product. In some embodiments, the amount of total impurities is less than about 1.7% or 1.6% in the final product. In some embodiments, the amount of total impurities is less than about 1.4% in the final product. In some embodiments, the amount of total impurities is less than about 1.33% in the final product. In some embodiments, the amount of total impurities is in the range of about 0.1% to about 10%, about 0.1% to about 8%, about 0.15 to about 1.6% in the final product.
- In some embodiments, the amount of compound A diastereomer is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.08%, 0.07%, 0.06%, 0.04%, 0.025% or 0.01% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.4% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.07% in the final product. In some embodiments, the amount of compound A diastereomer is less than about 0.05% in the final product. In some embodiments, the amount of compound A diastereomer is in the range of about 0.001% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.4% in the final product.
- In some embodiments, the amount of any single unknown impurity is less than about 10%, 8%, 6%, 5%, 4%, 3%, 2%, 1.5%, 1.2%, 1%, 0.9%, 0.8%, 0.7%, 6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.08%, 0.07%, 0.06%, 0.04%, 0.025% or 0.01% in the final product. In some embodiments, the amount of any single unknown impurity is less than about 0.4% in the final product. In some embodiments, the amount of any single unknown impurity is less than about 0.07% in the final product. In some embodiments, the amount of any single unknown impurity is less than about 0.05% in the final product. In some embodiments, the amount of any single unknown impurity is in the range of about 0.001% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.4% in the final product.
-
FIG. 1 is a non-limiting schematic of an apparatus for a continuous production process as described herein.FIG. 1 shows an apparatus 100 for production of a compound of Formula (Ia) or (Ib) or salt thereof, -
- wherein the apparatus 100 includes:
- a first vessel 101 comprising lithium amide;
- a second vessel 102 comprising a compound of Formula (IIa) or (IIb) or salt thereof;
-
- a
third vessel 105 comprising a compound of Formula (III) or salt thereof;
- a
-
A-O—C(O)—(CH2)nG -
- a first
continuous flow conduit 103 configured to be fluidly coupled to thefirst vessel 101 and thesecond vessel 102; and - a second
continuous conduit 104 configured to be fluidly coupled between the firstcontinuous flow conduit 103 and thethird vessel 105.
- a first
-
FIG. 2 is a non-limiting schematic of an apparatus for a continuous production process as described herein.FIG. 2 shows anapparatus 200 for production of a compound of Formula Ia or Ib or salt thereof, -
- wherein the
apparatus 200 includes: - a
first vessel 201 comprising lithium amide; - a
second vessel 202 comprising a compound of Formula (IIa) or (IIb) or salt thereof; - a
third vessel 205 comprising a compound of Formula (III) or salt thereof; - a
fourth vessel 206 comprising tetrahydrofuran; - a first
continuous flow conduit 203 configured to be fluidly coupled to thefirst vessel 201 and thesecond vessel 202; and - a second
continuous conduit 204 configured to be fluidly coupled between the firstcontinuous flow conduit 203 and thethird vessel 205.
- wherein the
- The apparatus described herein can optionally include one or more vessels containing the stock solutions of one or more reagents. In some embodiments, the apparatus described herein can further include a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit. In some embodiments, the apparatus described herein can include a fifth flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit.
- In some embodiments, the apparatus described herein can include optionally a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit, and wherein the third continuous flow conduit is configured to deliver the lithium amide from the first vessel to the first continuous flow conduit. In some embodiments, the apparatus described herein can optionally include a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit, and wherein the fourth continuous flow conduit is configured to deliver the compound of formula (IIa) or (IIb) from the second vessel to the first continuous flow conduit. In some embodiments, the apparatus described herein can include a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit, and wherein the fourth continuous flow conduit is configured to deliver the compound of formula (IIa) or (IIb) and/or trimethylsilyl chloride from the second vessel to the first continuous flow conduit. In some embodiments, the apparatus described herein can optionally include a fifth continuous flow conduit to fluidly couple the fourth vessel and the first continuous flow conduit, and wherein the fifth continuous flow conduit is configured to deliver the tetrahydrofuran solution from the fourth vessel to the first continuous flow conduit.
- In some embodiments, the apparatus described herein can optionally further include a sixth vessel fluidly coupled to the first vessel, wherein the sixth vessel comprises a stock solution of the lithium amide. In some embodiments, the apparatus described herein can optionally further include a seventh vessel fluidly coupled to the second vessel, wherein the seventh vessel comprises a stock solution of the compound of Formula (IIa) or (IIb). In some embodiments, the apparatus described herein can optionally further include an eighth vessel fluidly coupled to the second vessel, wherein the eighth vessel comprises a stock solution of the compound of trimethylsilyl chloride.
- One or more flow control members can be used in the apparatus to control the flow rate. The apparatus described herein can further include one or more flow control members fluidly coupled to the vessels comprising stock solutions of the lithium amide, tetrahydrofuran, trimethylsilyl chloride, or the compound of formula (IIa) or (IIb). The flow control members can be a pneumatic flow control including but not limited to a pressurized vessel; a valve; any pump known to be suitable for flow control, including but not limited to a syringe pump; any other flow control equipment known in the art; and combinations thereof.
- The vessel containing a stock solution can be pressurized depending on the flow control member used in the apparatus. In an embodiment wherein a valve is used to control the flow rate, a pressurized vessel containing a stock solution instead of a pump can be used in the apparatus described herein. In some embodiments, the vessel which comprises a stock solution of the lithium amide can be pressurized. In some embodiments, the vessel which comprises a stock solution of the compound of formula (IIa) or (IIb) can be pressurized. In some embodiments, the vessel which comprises a stock solution of the trimethylsilyl chloride compound can be pressurized. In some embodiments, the first vessel is pressurized. In some embodiments, the second vessel is pressurized. In some embodiments, the third vessel is pressurized. In some embodiments, the fourth vessel is pressurized. In some embodiments, the fifth vessel is pressurized. In some embodiments, the sixth vessel is pressurized. In some embodiments, the seventh vessel is pressurized. In some embodiments, the eighth vessel is pressurized.
- As shown in
FIG. 1 , thefirst vessel 101 is fluidly coupled to the firstcontinuous flow conduit 103 through avalve 101 a, and thesecond vessel 102 is fluidly coupled to thecontinuous flow conduit 103 through avalve 102 a. As shown inFIG. 2 , an additional vessel, thefourth vessel 206 for the tetrahydrofuran can be fluidly coupled to the first continuous flow conduit through avalve 206 a. - One or more vessels in the apparatus can be a continuous flow conduit. In some embodiments, the
first vessel continuous flow conduit first vessel continuous flow conduit second vessel continuous flow conduit second vessel continuous flow conduit third vessel continuous flow conduit continuous flow conduit third vessel first vessel second vessel third vessel - In some embodiments, the
fourth vessel 206 can optionally include a continuous flow conduit. In some embodiments, thefourth vessel 206 does not have a continuous flow conduit. - In some embodiments, for apparatus that includes a fifth vessel, the fifth vessel can optionally include a continuous flow conduit. In some embodiments, the fifth vessel is fluidly coupled to the first vessel and the fifth vessel comprises a stock solution of the lithium amide. In some embodiments, the sixth vessel can optionally include a continuous flow conduit. In some embodiments, for apparatus that includes a sixth vessel, the sixth vessel is fluidly coupled to the second vessel and the sixth vessel comprises a stock solution of the compound of formula (IIa) or (IIb). In some embodiments, for apparatus that includes a seventh vessel, the seventh vessel can optionally include a continuous flow conduit. In some embodiments, the seventh vessel is fluidly coupled to the second vessel and the seventh vessel comprises a stock solution of the trimethylsilyl chloride. In some embodiments, for apparatus that includes an eighth vessel, the eighth vessel can optionally include a continuous flow conduit. In some embodiments, the eighth vessel is fluidly coupled to the third vessel and the eighth vessel comprises a stock solution of tetrahydrofuran.
- The apparatus described herein can further include one or more cooling elements. In some embodiments, the cooling elements are thermally coupled to the first
continuous flow conduit continuous flow conduit first vessel second vessel third vessel fourth vessel 206. The apparatus described herein can further include a cooling element thermally coupled to thefourth vessel 106 or 206. The apparatus described herein can optionally further include a cooling element thermally coupled to the fifth, sixth, and seventh vessels. In an embodiment that a continuous flow of tetrahydrofuran is provided separately from a continuous flow of the lithium amide before the two flows are combined, the apparatus described herein can further include a cooling element thermally coupled to the alkyl amide solution vessel and the tetrahydrofuran solution vessel. - The apparatus described herein can further include one or more heating elements. In some embodiments, the heating element is used to warm up the reaction mixture that flows out of the first
continuous flow conduit continuous flow conduit third vessel - The apparatus described herein can further include a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere.
- The continuous flow conduit can be made of any suitable materials known in the art for conducting chemical reactions performed under low temperatures. In some embodiments, the continuous flow conduit can be made of stainless steel. In some embodiments, the first and second continuous flow conduits are made of stainless steel. In some embodiments, the first, the second, the third, and the fourth vessels are made of stainless steel.
- In some embodiments, the
third vessel third vessel - The dimension of the continuous flow conduit can vary depending on the reaction conditions and the production scale. Each continuous flow conduit can have a size that is different from or same as the other continuous flow conduit. In some embodiments, the continuous flow conduit is made of a tubing having a length in the range of about 0.1 m to about 50 m, about 0.1 m to about 25 m, or about 0.1 m to about 10 m. The tubing can be of straight or spiral.
- The apparatus described herein can include one or more valves positioned following the continuous flow conduit. In some embodiments, the apparatus described herein includes a valve immediately downstream of the first continuous flow conduit. In some embodiments, the apparatus described herein includes a valve immediately downstream of the second continuous flow conduit.
- The apparatus described herein can further include one or more flow control members fluidly coupled to the first, the second, the third, the fourth, the fifth, the sixth, or the seventh vessel. In some embodiments, the flow control member is fluidly coupled to the input of the first, the second, or the third vessel. In some embodiments, the flow control member is fluidly coupled to the output of the first, the second, or the third vessel. In some embodiments, the flow control member is fluidly coupled to at least one of the first, the second, and the third vessels. In some embodiments, the flow control member is fluidly coupled to the output of the fifth, sixth, or seventh vessel. In some embodiments, the flow control member is fluidly coupled to the input of the fourth vessel.
- In some embodiments, the apparatus here is used for the production of the compound of Formula (Ia). In some embodiments, the apparatus here is used for the production of the compound of Formula (Ib). In some embodiments, the second vessel includes the compound of Formula (IIa). In some embodiments, the second vessel includes the compound of Formula (IIb).
- The apparatus described herein can be used for production of the compound of formula (Ia) or (Ib) on a plant scale. The apparatus described herein can be used to produce more than about 10 kg, 100 kg, 250 kg, 500 kg, 800 kg of the compound of formula (Ia) or (Ib) per day.
- The following examples will further describe the present invention, and are used for the purposes of illustration only, and should not be considered as limiting.
- With reference to Table 1 below and the compounds shown in Comparative Example 1, an analytical method having parameters shown in Table 1 can be used to analyze samples taken from at various points in the flow process.
-
TABLE 1 An overview of the analytical method parameters Method B-2: Method A-1 and B-1: Compound A wt %, % a Final Product: Compound 2a wt % (derivatization, HPLC compound A wt %, % a (HPLC-CAD) UV) (HPLC UV) Column Phenomenex Kinetex C8 Phenomenex Kinetex C8 Phenomenex Kinetex C8 75 mm × 3.0 mm, 2.6 75 mm × 3.0 mm, 2.6 75 mm × 3.0 mm, 2.6 μm μm μm Column 1.0 ml/min 1.0 ml/min 1.0 ml/min Flow Column 15° C. 15° C. 15° C. Temperature wavelength n.a. (CAD) 235 nm 235 nm Injection 8 μL 8 μL 8 μL volume Eluent A Water + 0.1% formic Water + 0.1% formic Water + 0.1% formic acid acid acid Eluent B Acetonitrile + 0.1% Acetonitrile + 0.1% Acetonitrile + 0.1% formic acid formic acid formic acid Diluent Acetonitrile Acetonitrile Acetonitrile T T T (min) A B (min) A B (min) A B Gradient 0 40 60 0 40 60 0 40 60 8 25 75 8 25 75 8 25 75 12 10 90 12 10 90 12 10 90 16 10 90 16 10 90 16 10 90 16.1 40 60 16.1 40 60 16.1 40 60 20 40 60 20 40 60 20 40 60 Run time 20 min (4 min post run) 20 min (4 min post run) 20 min (4 min post run) - The reactions described in Scheme 2 were performed in a batch experiment.
- An approx. 27% solution of compound 2a in THE was mixed with a small amount of TMS-Cl (3 mol %) and cooled to −70° C. to −80° C. 1.10 equiv. (based on w % Compound 2a by HPLC) of a 25% solution of LHMDS in THE (pre-cooled to −10° C.) was dosed in a way that the reaction temperature was maintained below −70° C. After complete addition, the mixture was stirred for an additional 30 min at −70° C. and was analyzed for residual Compound 2a by method A (≤2.5% % wt compound 2a remaining). A sample of the reaction mixture was taken to determine whether any additional amount of LHMDS should be added. Then the mixture was warmed to ambient temperature and further stirred (typically: 1-3 h), until complete conversion was detected by chromatography.
- For preparation of Compound 2e, a slurry of purified 2-thiophen-acetic acid and hydroxybenzotriazole in acetonitrile was pre-cooled to −5 to 5° C. and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI) was added in portions in a way that the temperature can be maintained at −5 to 5° C.
- The resulting mixture was further stirred for 2-5 h at −5 to 5° C. Finally, the aforementioned reaction mixture from step 1 was dosed to the compound 2d at −5 to 5° C., and the resulting slurry was stirred for 3 h at −5 to 5° C. and then warmed to ambient temperature.
- The mixture was quenched by addition of an approx. 5% aqueous NaHCO3 solution. Heptane was added, and the layers were separated. The upper product-containing organic layer was subsequently washed another two times with approx. 5% aqueous NaHCO3 and water, and filtered over carbon cartridges. Finally, a distillative solvent switch to heptane was performed under reduced pressure at T<40° C. (target: 20-25° C.), with verification of complete removal of acetonitrile with chromatography method A (A-2). The product usually started to precipitate at this stage. If precipitation did not begun, seed crystals were added to induce crystallization. The resulting product slurry was cooled to −5 to 5° C. and was further stirred for 2 h at that temperature. The product Compound A was collected by filtration, washed in portions with cold heptane and dried under reduced pressure at <45° C. The final product was analyzed using method A (A-3).
- The experimental set-
up 100 as schematically outlined inFIG. 1 was used. As shown inFIG. 1 , afirst vessel 101 is used for storing and providing the lithium bis(trimethylsilyl)amide solution (in THF), asecond vessel 102 is used for storing and providing a compound 2a solution in tetrahydrofuran. A firstcontinuous flow conduit 103 is used for mixing the lithium bis(trimethylsilyl)amide and compound 2a reagents and for delivering the reaction mixture to the next step. A secondcontinuous flow conduit 104 is used to warm up the reaction mixture that flows out of the firstcontinuous flow conduit 103 and to deliver the reaction mixture to the next step. Avessel 105 is used for carrying out the reaction of making compound 2e and for collecting the compound 2d that flows out of the secondcontinuous flow conduit 104 so that compound 2e and compound 2d can react to form compound A. - During the reaction process, the lithium bis(trimethylsilyl)amide stock solution in THF was continuously added into the reaction process from the
vessel 101 through avalve 101 a and the lithium bis(trimethylsilyl)amide was pre-cooled before reaching the firstcontinuous flow conduit 103; a compound 2a stock solution in THE was continuously added into the reaction process from thevessel 102 through avalve 102 a; the mixture of lithium bis(trimethylsilyl)amide and compound 2a continuously flowed through the firstcontinuous flow conduit 103, which was maintained at about −30° C. using a cooling bath 106. The reaction mixture flowed from the firstcontinuous conduit 103 to the secondcontinuous flow conduit 104, which was maintained at an ambient temperature or maintained between 20° C.-30° C. using a bath 107. The secondcontinuous flow conduit 104 was used to warm up the reaction mixture that flowed out of the firstcontinuous flow conduit 103. The reaction mixture was then delivered to avessel 105. Thevessel 105 was maintained at −5° C. to 5° C. and contained compound 2e. The mixture of compound 2d and compound 2e were stirred in the vessel for 2-5 hours before a sample was taken to determine the yield of compound A. As illustrated inFIG. 1 , a valve such as 101 a, 102 a, or 104 a can be used to fluidly couple to a vessel or to a continuous flow conduit to control the flow of the reaction solutions. Based on the reaction condition, the set-up may include only one of the threevalves valves valves additional valve 103 a may be optionally added between the first continuous flow conduit and the second continuous flow conduit. The set-up shown inFIG. 2 can optionally include one or more other valves (not shown in the figure) to control the flow of the reaction at one or more other points in the set-up. - The set-up was operated at constant flows and a cooling bath was used to pre-cool the solutions and to maintain the needed reaction temperature. The first part of the set-up, (for LHMDS addition) was operated at low temperature (low temperature flow reactor). Sections of the set-up, including the tubes for delivering the lithium bis(trimethylsilyl)amide and/or the compound 2a solution were pre-cooled to guarantee fast mixing of the two flows and an efficient heat transfer. The second part of the flow reactor, (for rearrangement reaction) was operated at elevated temperature (in this case at room temperature—RT flow reactor). The key element of this set-up was to warm up the reaction solution to target temperature. After the RT flow reactor run the solution was collected in a vessel and stirred at ambient temperature until full conversion was reached (based on chromatography method A in batch process on less than 1.0% wt of compound 2a remaining). This solution was then dosed to the solution of the ester 2e, which was prepared according to batch protocol and further treated as in the batch protocol.
- A method B (B-1) sample can be pulled after the low temperature reactor run to check the conversion rate. For further control over the reaction conditions method B was introduced: The method A sample was converted to the second reaction intermediate using the active ester and the sample was analyzed after completed amidation (in this case derivatization). This method gives an overview about the expected product quality and yield after the rearrangement reaction.
- The experimental set-
up 100 as schematically outlined inFIG. 1 was used. Thevessel 101 for storing and providing lithium bis(trimethylsilyl)amide (25% in THF) was set to be about 1.5-1.0 mol eq. of compound 2a. Thevessel 102 for compound 2a was diluted with THE to a final concentration of 27 w %. Both lithium bis(trimethylsilyl)amide and compound 2a solutions were precooled to the operating temperature “low temperature” of about −30° C. continuous flow conduit. The low temperature continuous flow conduit had a length of 12 m, diameter of 0.88 cm, which corresponded to a residence time of about 70 sec. The room temperature continuous flow conduit had a length of 12 m, diameter of about 1.73 cm, which corresponded to a residence time of 4.5 min. Two additional vessels (not shown inFIG. 1 ) were installed after the continuous flow conduit: one each for pre- and post-run (start and Shutdown sequence). The first vessel was used for collecting waste at the beginning of the run until all flows were properly established. The second vessel was used in case of a problem such as clogging, in which case an automatic shutdown sequence would be triggered. In the event of clogging, the flow would be diverted to the second vessel so that the product collected up to that point would not be contaminated. The reaction mixture was delivered to thevessel 105 and was stirred with compound 2e at room temperature. Twosample valves valve 103 a after the firstcontinuous flow 103 conduit and onevalve 104 a after the secondcontinuous flow conduit 104. - The reaction mixture was stirred for 10 min in the collection vessel, and sample analysis showed a typical impurity profile, meaning that no unknown impurities were detected. Analysis of samples taken after the first continuous flow conduit using method A showed a very small amount of compound 2a remaining. Results of the residual amount of compound 2a detected in the process are shown in Table 2.
-
TABLE 2 Residual amount of compound 2a detected in the process After first After second After After continuous continuous 10 min in 60 min in flow conduit flow conduit collection collection 103 104 vessel vessel (Method B-1) (Method A-1) (20° C.) (20° C.) Residual 0.36 0.06 0.12 0.12 compound 2a (wt %) - The experimental set-
up 200 as schematically outlined inFIG. 2 was used. As shown inFIG. 2 , afirst vessel 201 is used for storing and providing the lithium bis(trimethylsilyl)amide solution (in THF), asecond vessel 202 is used for storing and providing a compound 2a solution in tetrahydrofuran. A firstcontinuous flow conduit 203 is used for mixing the lithium bis(trimethylsilyl)amide and compound 2a reagents and for delivering the reaction mixture to the next step. A secondcontinuous flow conduit 204 is used to warm up the reaction mixture that flows out of the firstcontinuous flow conduit 203 and to deliver the reaction mixture to the next step. Avessel 205 is used for carrying out the reaction of making compound 2e and for collecting the compound 2d that flows out of the secondcontinuous flow conduit 204 so that compound 2e and compound 2d can react to form compound A. Anadditional vessel 206 is used for storing and providing a separate stream THE solution to be combined with the lithium bis(trimethylsilyl)amide solution (in THF). - During the reaction process, the lithium bis(trimethylsilyl)amide stock solution in THF was continuously added into the reaction process from the
vessel 201 through avalve 201 a and a separate THE stock solution was stored invessel 206 and was continuously added into the reaction process to dilute the lithium bis(trimethylsilyl)amide in the flow stream before lithium bis(trimethylsilyl)amide was mixed with the compound 2a. The diluted lithium bis(trimethylsilyl)amide solution was pre-cooled to −30° C. before reaching the firstcontinuous flow conduit 203. A The compound 2a stock solution in THE was continuously added into the reaction process from thevessel 202 through avalve 202 a; the mixture of lithium bis(trimethylsilyl)amide (diluted) and compound 2a continuously flowed through thecontinuous flow conduit 203, which was is maintained at about −30° C. using a cooling bath 207. The reaction mixture flowed from the firstcontinuous conduit 203 to the secondcontinuous flow conduit 204, which was maintained at an ambient temperature or maintained between 20° C.-30° C. using a bath 208. The secondcontinuous flow conduit 204 was used to warm up the reaction mixture that flowed out of the firstcontinuous flow conduit 203. The reaction mixture was then delivered to avessel 205. Thevessel 205 was maintained at −5° C. to 5° C. and contained compound 2e. Compound 2d was then delivered from the secondcontinuous conduit 204 into thevessel 205 to react with compound 2e. As illustrated inFIG. 2 , a valve such as 201 a, 202 a, 204 a, 206 a can be used to fluidly couple to a vessel or to a continuous flow conduit to control the flow of the reaction solutions. Based on the reaction conditions, the set-up may include only one of the fourvalves valves valves valves additional valve 203 a may be optionally added between the first continuous flow conduit and the second continuous flow conduit. The set-up shown inFIG. 2 can optionally include one or more other valves (not shown in the figure) to control the flow of the reaction at other points in the set-up. - When additional flow of THE was introduced into the flow from the
third vessel 206 before combining the lithium bis(trimethylsilyl)amide and the compound 2a, dilution of the lithium amide may prevent blocking of the first continuous flow conduit maintained at lower temperatures and has therefor a positive influence on the robustness of the process. The flow setting was set to have the lithium bis(trimethylsilyl)amide to be 1.10 eq. of compound 2a, and the lithium bis(trimethylsilyl)amide (LHDMS) had a concentration of 17% after mixing with the separate steam of THF. A higher level of LHMDS with a molecular ration of 1.18 eq of compound 2a was also tested. Table 3 shows the results of the process with THE introduced to dilute the lithium amide. - After complete conversion the samples were converted to the final product using the active ester compound 2e to evaluate the product quality and impurity profile of the final product compound A. For sample derivatization the same stoichiometry and reaction conditions were used as for the batch compound A synthesis, and the product was analyzed from solution after amidation. The small-scale derivatization procedure for analysis method A shown in Table 1 was used, and samples were then compared to the data from the isolated product.
-
TABLE 3 Experiment parameters for reaction process with THF introduced to dilute the lithium amide Sample 3 Sample 1 Sample 2 Sample 3 (isolated) LT (° C.) −30 −30 −30 −30 RT (° C.) 20 20 20 20 LiHMDS 1.46 1.57 1.46 1.46 (ml/min) THF (ml/min) 0.67 0.67 0.67 0.67 Compound 2a 3.89 3.89 3.89 3.89 (ml/min) Compound 2a 27.12% 27.12% 27.12% 27.12% (g/g) Time LT (sec) 72.06 70.74 72.06 72.06 Time RT (min) 4.49 4.41 4.49 4.49 Eq LiHMDS/ 1.10 1.17 1.18 1.18 compound 2a Residual 1.10 0.22 0.97 NA compound 2a (wt %) Yield of 52.37% 51.12% 63.85% 63.79% compound A (method A) By product 2.8 4.4 2.7 0.86 (a %) - In addition, high concentration of lithium bis(trimethylsilyl)amide may lead to an increase in the amount of by-product formed. One by-product can be formed via α-deprotonation followed by elimination when excessive lithium bis(trimethylsilyl)amide is used.
- This by-product compound S1 is depleted by approx. 70% in the crystallization step of compound A. The presence of increased amounts of the by-product can lead to difficulties in the crystallization of compound A and have therefore a strong influence on product yield.
- Another by-product resulting from the use of high concentration or excess of lithium salt such as (t-butyl lithium) may include the compound S2:
- Diluting the lithium amide flow with an additional stream of THE can help provide better control over the lithium amide concentration and stoichiochemistry. It also can help to enhance process robustness by preventing precipitation of LHMDS from blocking the continuous flow conduit.
- The experimental set-up as schematically outlined in
FIG. 1 was used except that the residence time in the second continuous flow conduit was adjusted in the continuous flow process. The residence time in the second continuous flow conduit (room temperature) was compared at 4.5 min and about 15 min. The results showed that having a residence time of 15 mins in the second continuous flow conduit increased the conversion rate and the yield of compound A. The results also indicated that the synthesis of compound 2d in the continuous flow conduits can achieve full conversion and did not require an additional collecting vessel or stirring time at ambient temperature. - The experimental set-up as schematically outlined in
FIG. 1 was used. Direct synthesis of compound A using the flow process was tested using the following steps: a certain amount of active ester compound 2e was synthesized in thecollection vessel 205 and the corresponding amount of compound 2d was collected in this vessel after flowing through the secondcontinuous flow conduit 204. After the required material was collected, the reaction mixture was treated according to batch protocol and Compound A was isolated after distillation and crystallization. The results are shown in Table 4. In Table 4, the quality and yield of the isolated product was compared to the data from the derivatization method used in method B, and the results proved that the data from method B analysis were reliable. -
TABLE 4 Experiment parameters for reaction process with direct synthesis of compound A in the collection vessel. Sample 2 Sample 1 Sample 2 (isolated) LT (° C.) −30 −30 −30 RT (° C.) 20 20 20 LiHMDS (ml/min) 1.6 1.6 1.6 THF (ml/min) 0.78 0.78 0.78 Compound 2a (ml/min) 3.57 3.57 3.57 Compound 2a in THF (wt %) 32 32 32 Time LT (sec) 72.06 72.06 72.06 Time RT (min) 15.06 15.06 15.06 Eq LiHMDS/compound 2a 1.11 1.11 1.11 Residual compound 2a (wt %) 0.70 0.63 NA Yield of compound A 55.28% 62.12% 59.93% (method A) By product (a %) 3.0 3.2 0.94 - The direct conversion of compound 2d to compound A can be achieved by collection of compound 2d in the active ester compound 2e solution in the
vessel 205. This process leads to reduction of reaction time, simplifying the process, and increasing the overall productivity. - The experimental set-up as schematically outlined in
FIG. 2 was used. Direct synthesis of compound A using the flow process was tested using the following steps shown in Table 5. All material equivalents were calculated based on the compound 2a wt % measured from HPLC-CAD analysis. The amount of compound 2a in the THF measured using HPLC-CAD was about 45.5% (wt), 39.3 mmol, and about 20.3 g. - The values in the process were based on 45 g compound 2a, which equaled to a 20 min run (the
vessels -
TABLE 5 Reaction Parameters for the direct synthesis of compound A using a continuous flow process Step Reagent Equipment inertization Preparation of Feed Solutions Charging of compound 2a as 45% solution Compound 2a in THF in THF to vessel 102 (compound 2a amount (45 g of compound 2a, determined by HPLC) volume 45 ml, 38.32 mmol) Charging of THF to vessel 102THF (16.87 g, 19.08 ml, and 5.95 mol eq) Charging TMSCl to vessel 102TMSCl (0.13 g, 0.12 ml, 0.18 mmol, and 0.03 mol eq) Charging of LHMDS as 25% solution in LHMDS about 25% THF to a vessel 101solution in THF (27.84 g, Reagent amount/compound 2a (by weight) = 31.17 ml, 43.25 mmol, about 1.37—the actually needed amount and 1.10 mol eq) depends on assay of compound 2a and LHMDS solution and is controlled with HPLC analysis (e.g. method A) Charging of THF to vessel 106 THF (12.14 g, 13.73 ml, Reagent amount/compound 2a (by weight) = 168.29 mol, 4.28 mol eq) 0.60 Performed for about 30 min Preparation of ester solution compound 2e Charging of compound purified 2-thiophen- 2-thiophen-acetic acid acetic acid (7.10 g, 49.94 mmol, 1.3 mol eq) Charging of HOBt•H2O HOBt (7.97 g, 51.9 mmol, 1.3 mol eq) Addition of acetonitrile-reactants to be Acetonitrile (31.75 g, 40.7 suspended ml, 773.4 mmol with a relative weight of about 2.01) Cooling to −5° C. to 5° C. Addition of EDC•HCI in portions with EDCl (11.91 g, 62.13 cooling, so that a temperature of −5° C. to mmol, 1.6 mol eq) 5° C. can be maintained (minor exothermic reaction observed) Stirring of the resulting suspension for 2-5 h at −5° C.-5° C. Continuous Flow Process to Prepare Compound 2d Set temperature of cooling bath to −30° C. (first continuous flow conduit 103) Set temperature of warming-up bath to 20° C. (second continuous flow conduit 104) Startup of flow reactor: a) Set valve to waste stream vessel b) Set THF flow (pressure vessel 104) = 0.69 g/min c) Set compound 2a in THF flow (pressure vessel 101) = 3.21 g/min d) Set LHMDS/THF flow (pressure vessel 102) = 1.43 g/min e) Wait for constant flows/pressure f) Set valve to collection vessel HPLC (Method B): conversion of compound 2a after first continuous flow conduit run HPLC (Method B): Derivatization with active ester compound 2e Collection time: Collect reaction solution during stable state from the continuous flow conduit in vessel 105 for about 20 min Shut down of flow reactor: a) Set LHMDS/THF flow (pressure vessel 101) = 0 g/min b) Set compound 2a in THF flow (pressure vessel 102) = 0 g/min c) Wait for last compound 2a in THF to reach end of flow reactor d) Set valve to waste stream vessel e) Flush flow reactor with THF to waste stream vessel f) Set THF flow (pressure vessel 106) = 0 g/min Amide coupling (compound 2d-compound A) Collect flow stream in active ester Reaction mixture compound 2e solution obtained above at containing compound 2d −5° C. to 5° C. can be maintained (94.15 ml run for 20 min) Stirring of reaction mixture for ≥3 h at −5° C. to 5° C. Warming of reaction mixture to 18° C. to 24° C. (overnight) Extraction Work-up and Carbon filtration Addition of 5% NaHCO3 solution 5% NaHCO3 (about 47.8 g, 47.8 ml, 28.4 mmol, relative vol 2.36) Addition of heptane heptane (32.7 g, 47.7 ml, 327.1 mmol, relative vol 2.36) Rinse line with heptane heptane (318.48 g, 26.93 ml, 184.4 mmol, relative vol 1.33) Phase separation-removal of lower aqueous layer Addition of 5% NaHCO3 solution 5% NaHCO3 (about 47.8 g, 47.8 ml, 28.4 mmol, relative vol 2.36) Phase separation-removal of lower aqueous layer Repeat the addition of NaHCO3 solution and phase separation steps Addition of water Water (47.8 g, 47.8 ml, 2652.4 mmol, rel. vol. 2.36) Phase separation-removal of lower aqueous layer Filtration of product containing organic Carbon (2.03 g, rel. wt. layer over Carbon Cartridge (Carbofil PHA 0.10) I Filtrox) Rinse of filter with heptane heptane (16.4 g, 23.9 ml, 163.6 mmol, rel. vol. 1.18) Distillative concentration in vacuo at Target col. 47.78 ml (rel <40° C. until target volume 80 mL/33.9 g vol. 2.36) ( compound 2a 100% conversion)Lab: T M = 40° C./300-200 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) Check for crystallization initialization (if Compound A seeds necessary, addition of seeds) (0.006 g, 0.01 mmol) Distillative concentration in vacuo at Target col. 68.7 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./180-130 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) Distillative concentration in vacuo at Target col. 68.7 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./130-95 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) Distillative concentration in vacuo at Target col. 68.7 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./95 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) GC analysis: Acetonitrile ≤0.10 wt % (on heptane) If necessary, repeat last cycle of heptane addition + distillation Crystallization Stirring of product suspension for lh at 18-24° C. Cooling to −5-5° C. (alternatively: −15° C.} Stirring for 2 h Product filtration Washing of filter cake with cold heptane heptane (46.3 g, 67.4 ml) (in portions) Product Drying Drying of wet product in vacuo at <45° C. LOD analysis: ≤1.0% OLD Discharging of dry product compound A Compound A (14.62 g, 23.6 mmol) - The experimental set-up as schematically outlined in
FIG. 2 was used. Direct synthesis of compound A using the flow process was tested using the following steps shown in Table 6. All material equivalents were calculated based on the compound 2a wt % measured from HPLC-CAD analysis. The amount of compound 2a in the THF measured using HPLC-CAD was about 53.2% (wt), 40.4 mmol, and about 20.8 g. - The values in the process were based on 39.1 g compound 2a, which equaled to a 20 min run (the
vessels -
TABLE 6 Reaction Parameters for the direct synthesis of compound A using a continuous flow process Step Reagent Equipment inertization Preparation of Feed Solutions Charging of compound 2a as 53% solution Compound 2a in THF in THF to vessel 102 (compound 2a amount (39.1 g of compound 2a, determined by HPLC) volume 41.16 ml, 40.24 Reagent amount/compound 2a = 1.89 mmol) Charging of THF to vessel 102THF (25.82 g, 29.21 ml, Reagent amount/compound 2a (by weight) = and 8.9 mol eq) 0.83 Charging of LHMDS as 19% solution in LHMDS about 19% THF to a vessel 101solution in THF Reagent amount/compound 2a (by weight) = (35.35 g, 39.58 ml, 42.25 about 1.77—the actually needed amount mmol, and 1.05 mol eq) depends on assay of compound 2a and LHMDS solution and is controlled with HPLC analysis (e.g. method A) Preparation of ester solution-compound 2e Charging of compound purified 2- 2-Thienylacetic acid (7.27 Thienylacetic acid g, 51.10 mmol, 1.27 mol eq) Charging of HOBt•H2O HOBt (8.16 g, 53.12 mmol, 1.32 mol eq) Addition of acetonitrile-reactants to be Acetonitrile (32.49 g, suspended 41.65 ml, 794.46 mmol with a relative weight of about 2.01) Cooling to −5° C. to 5° C. Addition of EDC•HCl in portions with EDCI (12.19 g, 63.59 cooling, so that a temperature of −5° C. to mmol, 1.58 mol eq) 5° C. can be maintained (minor exothermic reaction observed) Stirring of the resulting suspension for 2-5 h at −5° C.-5° C. Continuous Flow Process to Prepare Compound 2d Set temperature of cooling bath to −10° C. (first continuous flow conduit 103) Set temperature of warming-up bath to 20° C. (second continuous flow conduit 104) Startup of flow reactor: a) Set valve to waste stream vessel b) Set THF flow (pressure vessel 104) = 0.69 g/min c) Set compound 2a in THF flow (pressure vessel 101) = 3.57 g/min d) Set LHMDS/THF flow (pressure vessel 102) = 1.87 g/min e) Wait for constant flows/pressure f) Set valve to collection vessel IPC-1 (HPLC): sampling after the first continuous flow conduit HPLC (Method B): conversion of compound 2a after first continuous flow conduit run (≤1% wt compound 2a left unreacted according to the reaction in batch) HPLC (Method B): Derivatization with active ester compound 2e Collection time: once stable-state achieved, collect reaction solution from the continuous flow conduit in vessel 105 for about 20 min Shut down of flow reactor: a) Set LHMDS/THF flow (pressure vessel 101) = 0 g/min b) Set compound 2a in THF flow (pressure vessel 102) = 0 g/min c) Wait for last compound 2a in THF to reach end of flow reactor d) Set valve to waste stream vessel e) Flush flow reactor with THF to waste stream vessel f) Set THF flow (pressure vessel 106) = 0 g/min (vessel only used for startup and shut down sequence) Amide coupling (compound 2d-compound A) Collect flow stream in active ester Reaction mixture compound 2e solution obtained above at containing compound 2d −5° C. to 5° C. can be maintained (101.60 ml run for 20 min) Stirring of reaction mixture for ≥3 h at −5° C. to 5° C. Warming of reaction mixture to 18° C. to 24° C. (overnight) Extraction Work-up and Carbon filtration Addition of 5% NaHCO3 solution 5% NaHCO3 (about 48.98 g, 48.98 ml, 29. mmol, relative vol 2.36) Addition of heptane heptane (333.54 g, 48.89 ml, 334.69 mmol, relative vol 2.36) Stir (15 min) and settle (15 min) Phase separation-removal of lower aqueous layer Addition of 5% NaHCO3 solution 5% NaHCO3 (about 48.98 g, 48.98 ml, 29. mmol, relative vol 2.36) Stir (15 min) and settle (15 min) Phase separation-removal of lower aqueous layer Repeat the addition of NaHCO3 solution and phase separation steps Addition of water Water (48.98 g, 48.98 ml, 29. mmol, relative vol 2.36) Phase separation-removal of lower aqueous layer Distillative concentration in vacuo at Target col. 47.78 ml (rel <40° C. until target volume 80 mL/33.9 g vol. 2.36) ( compound 2a 100% conversion)Addition of heptane heptane (48.4 g, 70.55 ml, relative vol 3.39) Check for crystallization initialization (if Compound A seeds (0.006 necessary, addition of seeds) g, 0.01 mmol) Distillative concentration in vacuo at Target col. 70.55 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./180-130 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) Distillative concentration in vacuo at Target col. 70.55 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./130-95 mbar Addition of heptane heptane (48.4 g, 70.55 ml, relative vol 3.39) Distillative concentration in vacuo at Target col. 70.55 ml (rel <40° C. until target volume about 115 mL/ vol. 3.39) 33.9 g Lab: T M = 40° C./95 mbar Addition of heptane heptane (47.1 g, 68.7 ml, relative vol 3.39) GC analysis: Acetonitrile ≤0.10 wt % If necessary, repeat last cycle of heptane addition + distillation Crystallization Stirring of product suspension for lh at 18-24° C. Cooling to −5-5° C. Stirring for 2 h Product filtration Washing of filter cake with cold heptane (in heptane (47.52 g, 69.27 ml) portions) Product Drying Drying of wet product in vacuo at <45° C. LOD analysis: ≤1.0% OLD Discharging of dry product compound A Compound A (14.62 g, 23.6 mmol) - The amount of compound A obtained was about 18.07 g, and the yield based on HPLC analysis is about 72.89%. The purity of the final product compound A, based on HPLC analysis was about 99.9%.
Claims (42)
1. An apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof,
wherein:
Q is —(CH2)m—;
M is —CH2— or —CH═CH—;
m is 1 or 2;
R1 is a carboxyl protecting group;
R2 is a hydroxyl protecting group; or
R1 and R2 together with the atoms to which they are attached form a heterocyclic ring optionally substituted with C1-4 alkyl;
each R3 is independently selected from hydrogen, —OH, halogen, —CF3, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl, 5-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, cyano, C1-C6 alkoxy(C1-C6)alkyl, C6-10 aryloxy, sulfhydryl (mercapto), and —(CH2)m′—Y′—(CH2)pM′;
m′ and p are independently 0 to 3;
Y′ is selected from the group consisting of —S—, —S(O)—, —S(O)2—, —O—, —CR4aR5a—, and
—NR1a—;
M′ is selected from the group consisting of —C(O)NR1aR2a; —C(O)NR1aOR3a; —NR1aC(O)R4a; —NR1aC(O)NR2aR1b; —NR1aC(O)OR3a; —NR1aS(O)2R3a; —NR1aS(O)2NR2aR1b;
—C(═NR1a)R4a; —C(═NR1a)NR2aR1b; —NR1aCR4a(═NR2a); —NR1aC(═NR2a)NR1bR2b; C1-4 alkyl optionally substituted with 0-2 substituents selected from the group consisting, —OR3a,
—NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; C3-10 cycloalkyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a; C6-10 aryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen,
—C(O)NR1aR2a, and —NR1aC(O)R4a; 5 to 10 membered heteroaryl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen,
—C(O)NR1aR2a, and —NR1aC(O)R4a; and 4 to 10 membered heterocyclyl optionally substituted with 0-2 substituents selected from the group consisting of C1-4 alkyl, —OR3a, —NR1aR2a, halogen, —C(O)NR1aR2a, and —NR1aC(O)R4a;
each R1a, R2a, R1b and R2b are independently selected from the group consisting of —H, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
R3a is hydrogen, optionally substituted C1-10alkyl, -optionally substituted C1-10alkyl-COOH, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl; and
each R4a and R5a is independently selected from the group consisting of —H, —OH, optionally substituted alkoxyl, optionally substituted —C1-10alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10aryl, and optionally substituted 5-10 membered heteroaryl;
n is 0 to 3;
G is selected from the group consisting of —NR1R2, —N3, —C(O)NR1R2, —S(O)2NR1R2, —SR3, —OR3, —CH2NR1C(O)R5, —C(═NOR3)—X, C(═NOR3)—Z, —C(O)OR3, —C(O)NR1(OR3),
—NR1(OR3), —NR1C(O)R5, —NR1C(O)NR2R1a, —NR1C(O)OR3, —NR'S(O)2R3, —NR'S(O)2NR2R1a, —NR1NR2R1a, —C(O)NR1NR2R1a, —S(O)2NR1NR2R1a, —C(═NR1)R5, —C(═NR1)NR2R1a, —NR1CR5(═NR2), —NR1C(═NR2)NR1aR2a, optionally substituted C1-10 alkyl, optionally substituted C2-10alkenyl, optionally substituted C2-10alkynyl, optionally substituted C3-7 carbocyclyl, optionally substituted 5-10 membered heterocyclyl, optionally substituted C6-10aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6alkylene-C3-7carbocyclyl, optionally substituted C1-6alkylene-5-10 membered heterocyclyl, optionally substituted C1-6alkylene-C6-10aryl, and optionally substituted C1-6alkylene-5-10 membered heteroaryl;
X is hydrogen or optionally substituted C1-9alkyl;
Z is selected from optionally substituted C3-8 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl;
the apparatus comprising:
a first vessel comprising a lithium amide;
a second vessel comprising a compound of Formula (IIa) or (IIb) or salt thereof;
a third vessel comprising a compound of Formula (III) or salt thereof;
A-O—C(O)—(CH2)nG (III)
A-O—C(O)—(CH2)nG (III)
wherein A is a C6-10aryl, 5-10 membered heteroaryl, C3-7carbocyclyl, or 5-10 membered heterocyclyl;
a first continuous flow conduit fluidly coupled to the first vessel and the second vessel; and
a second continuous conduit fluidly coupled between the first continuous flow conduit and the third vessel.
2. An apparatus for production of a compound of Formula (Ia) or (Ib) or salt thereof,
Comprising:
a first continuous flow conduit;
a second continuous flow conduit extending from the first continuous flow conduit to a discharge end,
a first vessel comprising a lithium amide and configured to deliver the lithium amide compound to the first continuous flow conduit;
a second vessel comprising a compound of Formula (IIa) or (IIb) or salt thereof and configured to deliver the compound of Formula (IIa) or (IIb) or salt thereof to the first continuous flow conduit; and
3. The apparatus of claim 1 , further comprising a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit.
4. The apparatus of claim 3 , further comprising a fifth continuous flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit.
5. The apparatus of claim 3 , wherein the fourth vessel is pressurized.
6. The apparatus of claim 1 , further comprising a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit and to deliver the lithium amide from the first vessel to the first continuous flow conduit.
7. The apparatus of claim 6 , wherein the first vessel is pressurized.
8. The apparatus of claim 4 , further comprising a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit and to deliver the compound of Formula (IIa) or (IIb) or salt thereof from the second vessel to the first continuous flow conduit.
9. The apparatus of claim 8 , wherein the second vessel is pressurized.
10. The apparatus of claim 1 , further comprising one or more cooling elements thermally coupled to the first continuous flow conduit.
11. The apparatus of claim 8 , further comprising one or more cooling elements thermally coupled to at least one of the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit.
12. The apparatus of claim 1 , further comprising a heating element thermally coupled to the second continuous flow conduit.
13. The apparatus of claim 1 , further comprising one or more cooling elements thermally coupled to at least one of the first and the second continuous flow conduit.
14. The apparatus of claim 3 , further comprising a cooling element thermally coupled to the fourth vessel.
15. The apparatus of claim 14 , wherein the cooling element comprises a cooling bath.
16. The apparatus of claim 1 , further comprising one or more flow control members fluidly coupled to at least one of the first, the second, and the third vessels.
17. The apparatus of claim 1 , further comprising a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere.
18. The apparatus of claim 1 , wherein the first and second continuous flow conduits are made of stainless steel.
19. The apparatus of claim 1 , wherein the first and the second vessels are made of stainless steel.
20. The apparatus of claim 3 , wherein the fourth vessel is not a continuous flow conduit and does not comprise a continuous outflow.
21. The apparatus of claim 3 , wherein the fourth vessel comprises the compound of Formula (IIa) or salt thereof.
23. The apparatus of claim 2 , further comprising a fourth vessel, wherein the fourth vessel comprises tetrahydrofuran and is fluidly coupled with the first vessel to combine the lithium amide and the tetrahydrofuran before the lithium amide flowing into the first continuous flow conduit.
24. The apparatus of claim 23 , further comprising a fifth continuous flow conduit, wherein the fifth continuous flow conduit is fluidly coupled the fourth vessel and the first continuous flow conduit to deliver the tetrahydrofuran from the fourth vessel to the first continuous flow conduit.
25. The apparatus of claim 3 , wherein the fourth vessel is pressurized.
26. The apparatus of claim 2 , further comprising a third continuous flow conduit to fluidly couple the first vessel and the first continuous flow conduit and to deliver the lithium amide from the first vessel to the first continuous flow conduit.
27. The apparatus of claim 6 , wherein the first vessel is pressurized.
28. The apparatus of claim 24 , further comprising a fourth continuous flow conduit to fluidly couple the second vessel and the first continuous flow conduit and to deliver the compound of Formula (IIa) or (IIb) or salt thereof from the second vessel to the first continuous flow conduit.
29. The apparatus of claim 8 , wherein the second vessel is pressurized.
30. The apparatus of claim 2 , further comprising one or more cooling elements thermally coupled to the first continuous flow conduit.
31. The apparatus of claim 28 , further comprising one or more cooling elements thermally coupled to at least one of the third continuous flow conduit, the fourth continuous flow conduit, and the fifth continuous flow conduit.
32. The apparatus of claim 2 , further comprising a heating element thermally coupled to the second continuous flow conduit.
33. The apparatus of claim 2 , further comprising one or more cooling elements thermally coupled to at least one of the first and the second continuous flow conduit.
34. The apparatus of claim 23 , further comprising a cooling element thermally coupled to the fourth vessel.
35. The apparatus of claim 14 , wherein the cooling element comprises a cooling bath.
36. The apparatus of claim 2 , further comprising one or more flow control members fluidly coupled to at least one of the first, the second, and the third vessels.
37. The apparatus of claim 2 , further comprising a gas purging member configured to purge the apparatus with nitrogen or argon atmosphere.
38. The apparatus of claim 2 , wherein the first and second continuous flow conduits are made of stainless steel.
39. The apparatus of claim 2 , wherein the first and the second vessels are made of stainless steel.
40. The apparatus of claim 23 , wherein the fourth vessel is not a continuous flow conduit and does not comprise a continuous outflow.
41. The apparatus of claim 23 , wherein the fourth vessel comprises the compound of Formula (IIa) or salt thereof.
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US17/698,719 US20220204534A1 (en) | 2017-02-01 | 2022-03-18 | Apparatus and continuous flow process for production of boronic acid derivative |
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US201762453408P | 2017-02-01 | 2017-02-01 | |
PCT/US2018/016246 WO2018144607A1 (en) | 2017-02-01 | 2018-01-31 | Apparatus and continuous flow process for production of boronic acid derivative |
US201916482195A | 2019-07-30 | 2019-07-30 | |
US17/698,719 US20220204534A1 (en) | 2017-02-01 | 2022-03-18 | Apparatus and continuous flow process for production of boronic acid derivative |
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US4783443A (en) | 1986-03-03 | 1988-11-08 | The University Of Chicago | Amino acyl cephalosporin derivatives |
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DE10139664A1 (en) * | 2001-08-11 | 2003-02-20 | Clariant Gmbh | Preparation of aryl- or alkyl-boron compounds via lithioaromatics or lithiated aliphatics is effected in microreactors with long, narrow capillaries to ensure intensive mixing and so reduce by-product content |
CN102245616B (en) * | 2008-12-25 | 2016-03-30 | 日本曹达株式会社 | The manufacture method of organolithium compound and the manufacture method of substituted aromatic compound |
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EP2755980B1 (en) | 2011-09-14 | 2019-10-30 | Dow AgroSciences LLC | Methods and systems for forming boronic acids and intermediates thereof |
JP2016509594A (en) * | 2013-01-04 | 2016-03-31 | レンペックス・ファーマシューティカルズ・インコーポレイテッド | Boronic acid derivatives and their therapeutic use |
US9101638B2 (en) | 2013-01-04 | 2015-08-11 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
PL3140310T3 (en) | 2014-05-05 | 2020-01-31 | Rempex Pharmaceuticals, Inc. | Synthesis of boronate salts and uses thereof |
US9963467B2 (en) | 2014-05-19 | 2018-05-08 | Rempex Pharmaceuticals, Inc. | Boronic acid derivatives and therapeutic uses thereof |
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US10662205B2 (en) | 2014-11-18 | 2020-05-26 | Qpex Biopharma, Inc. | Cyclic boronic acid ester derivatives and therapeutic uses thereof |
US10364257B2 (en) | 2014-12-19 | 2019-07-30 | Rempex Pharmaceuticals, Inc. | Apparatus and continuous flow process for production of boronic acid derivatives |
US10294249B2 (en) | 2016-06-30 | 2019-05-21 | Qpex Biopharma, Inc. | Boronic acid derivatives and therapeutic uses thereof |
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BR112019015577B8 (en) | 2023-11-14 |
CL2020001209A1 (en) | 2020-11-06 |
US11352373B2 (en) | 2022-06-07 |
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