TW202206420A - Intermediates and methods for preparing a glp-1 receptor agonist - Google Patents
Intermediates and methods for preparing a glp-1 receptor agonist Download PDFInfo
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- TW202206420A TW202206420A TW110119058A TW110119058A TW202206420A TW 202206420 A TW202206420 A TW 202206420A TW 110119058 A TW110119058 A TW 110119058A TW 110119058 A TW110119058 A TW 110119058A TW 202206420 A TW202206420 A TW 202206420A
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- 238000000034 method Methods 0.000 title claims abstract description 100
- 239000000543 intermediate Substances 0.000 title abstract description 4
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 title abstract 2
- 239000003877 glucagon like peptide 1 receptor agonist Substances 0.000 title abstract 2
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- PDBXHPORMXSXKO-UHFFFAOYSA-N 8-benzyl-7-[2-[ethyl(2-hydroxyethyl)amino]ethyl]-1,3-dimethylpurine-2,6-dione;hydron;chloride Chemical class Cl.N=1C=2N(C)C(=O)N(C)C(=O)C=2N(CCN(CCO)CC)C=1CC1=CC=CC=C1 PDBXHPORMXSXKO-UHFFFAOYSA-N 0.000 claims description 15
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- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 3
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- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960002428 fentanyl Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
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- 125000001478 1-chloroethyl group Chemical group [H]C([H])([H])C([H])(Cl)* 0.000 description 1
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- UKFTXWKNVSVVCJ-UHFFFAOYSA-N 2-[(6-hydrazinylpyridazin-3-yl)-(2-hydroxyethyl)amino]ethanol;hydron;dichloride Chemical class Cl.Cl.NNC1=CC=C(N(CCO)CCO)N=N1 UKFTXWKNVSVVCJ-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
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- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229940073735 4-hydroxy acetophenone Drugs 0.000 description 1
- OBMZMSLWNNWEJA-XNCRXQDQSA-N C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 Chemical compound C1=CC=2C(C[C@@H]3NC(=O)[C@@H](NC(=O)[C@H](NC(=O)N(CC#CCN(CCCC[C@H](NC(=O)[C@@H](CC4=CC=CC=C4)NC3=O)C(=O)N)CC=C)NC(=O)[C@@H](N)C)CC3=CNC4=C3C=CC=C4)C)=CNC=2C=C1 OBMZMSLWNNWEJA-XNCRXQDQSA-N 0.000 description 1
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- 101710176384 Peptide 1 Proteins 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910000318 alkali metal phosphate Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000316 alkaline earth metal phosphate Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
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- 238000005893 bromination reaction Methods 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
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- 238000001816 cooling Methods 0.000 description 1
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- 125000004122 cyclic group Chemical group 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical compound C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
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- 239000012973 diazabicyclooctane Substances 0.000 description 1
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 1
- YKVPQLOCTCSVAB-UHFFFAOYSA-N dichloromethane;2-methoxy-2-methylpropane Chemical compound ClCCl.COC(C)(C)C YKVPQLOCTCSVAB-UHFFFAOYSA-N 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
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- 230000005484 gravity Effects 0.000 description 1
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- 125000005842 heteroatom Chemical group 0.000 description 1
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- 238000002955 isolation Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- SXQFCVDSOLSHOQ-UHFFFAOYSA-N lactamide Chemical class CC(O)C(N)=O SXQFCVDSOLSHOQ-UHFFFAOYSA-N 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FXSZGKYGUFCBQY-UHFFFAOYSA-N propanoic acid;dihydrochloride Chemical compound Cl.Cl.CCC(O)=O FXSZGKYGUFCBQY-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本發明屬於藥物合成領域，並且具體地涉及用於製備(S)-2-(3S,8S)-3-(4-(3,4-二氯苄基氧基)苯基-7-((S)-1-苯基丙基)-2,3,6,7,8,9-六氫-[1,4]-二氧雜環己二烯並[2,3-g]異喹啉-8-基甲醯氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二鹽酸鹽的中間體和方法。The present invention belongs to the field of pharmaceutical synthesis, and particularly relates to a method for preparing (S)-2-(3S,8S)-3-(4-(3,4-dichlorobenzyloxy)phenyl-7-(( S)-1-Phenylpropyl)-2,3,6,7,8,9-hexahydro-[1,4]-dioxo[2,3-g]isoquinoline Intermediates and methods for -8-ylcarbamoylamino)-3-(4-(2,3-lutidine-4-yl)phenyl)propanoic acid dihydrochloride.
(S)-2-(3S,8S)-3-(4-(3,4-二氯苄基氧基)苯基-7-((S)-1-苯基丙基)-2,3,6,7,8,9-六氫-[1,4]-二氧雜環己二烯並[2,3-g]異喹啉-8-基甲醯氨基)-3-(4-(2,3-二甲基吡啶-4-基)苯基)丙酸二鹽酸鹽 (「OAD2二鹽酸鹽」) 是口服的、非肽類升糖素胜肽1(GLP-1)受體促效劑。OAD2二鹽酸鹽具有分子式C50
H49
Cl4
N3
O6
，分子量929.76，以及下面的化學結構：
發明專利CN102378574B(及相關的國際公開WO2010/114824)公開了製備OAD2的方法(總結在方案1中)，其使用4-羥基苯乙酮作為起始材料並包括14個步驟，所述步驟包括親核取代、溴化、不對稱還原、縮合、水解等。
然而，方案1中的製備方法包括許多步驟，需要多次管柱層析分離，並且具有僅5%的總產率，這使得其難以應用於工業生產。因此，有必要重新開發適合工業生產的合成路線。However, the preparation method in Scheme 1 includes many steps, requires multiple column chromatography separations, and has an overall yield of only 5%, which makes it difficult to apply to industrial production. Therefore, it is necessary to re-develop synthetic routes suitable for industrial production.
本發明提供了製備OAD2二鹽酸鹽的方法。與現有技術相比較，所述方法具有更少的步驟和增加的產率，並且採用了多步連續進料反應，所述多步連續進料反應不需要管柱層析分離，並且適合工業生產。另外，所述方法使用不同於先前公開的路徑來加入對掌中心。The present invention provides a method for preparing OAD2 dihydrochloride. Compared with the prior art, the method has fewer steps and increased yield, and employs a multi-step continuous feed reaction that does not require column chromatography separation and is suitable for industrial production . In addition, the method uses a different path than previously disclosed to add the center of the palm.
在第一態樣，本發明提供了製備式13化合物或其鹽類的方法：
在第二態樣，本發明提供了製備式14化合物或其鹽類的方法：
在第三態樣，本發明提供了製備式15化合物或其鹽類的方法：
在第四態樣，本發明提供了製備式8化合物或其鹽類的方法：
在第五態樣，本發明提供了製備式10化合物或其鹽類的方法：
在第六態樣，本發明提供了製備OAD2的單HCl鹽(式11化合物)的方法，其中所述方法包括第一步：水解式10化合物的甲基酯
在第七態樣，本發明提供了製備OAD2的雙HCl鹽的方法，其中所述方法包括將OAD2的單HCl鹽(式11化合物)與HCl反應，以製備OAD2的雙HCl鹽。In a seventh aspect, the present invention provides a method of preparing a bis-HCl salt of OAD2, wherein the method comprises reacting a mono-HCl salt of OAD2 (a compound of formula 11) with HCl to prepare a bis-HCl salt of OAD2.
根據本發明，具體的製備方法可以包括如下面的方案2中所示的態樣1至7中的一個或多個步驟。According to the present invention, a specific preparation method may include one or more steps in Aspects 1 to 7 as shown in Scheme 2 below.
在第八態樣，本發明提供了式13化合物和式14化合物。In an eighth aspect, the present invention provides compounds of formula 13 and compounds of formula 14.
定義definition
本文使用的術語「烷基」意指單價飽和的烴基團，其可以是直鏈或支鏈或它們的組合。除非另有定義，否則這些烷基通常含有1-12個碳原子。代表性的烷基包括，例如，甲基(Me)、乙基(Et)、正丙基((n-Pr)或(nPr))、異丙基((i-Pr)或(iPr))、正丁基((n-Bu)或(nBu))、仲丁基、異丁基、叔丁基((t-Bu)或(tBu))、正戊基、正己基、2,2-二甲基丙基、2-甲基丁基、3-甲基丁基、2-乙基丁基、2,2-二甲基戊基、2-丙基戊基等。當特定數量的碳原子用於具體的術語時，碳原子的數量展示在該術語的前面。例如，術語「C1-3 烷基」意指具有1至3個碳原子的烷基，其中所述碳原子處於任何化學上可接受的構型，包括直鏈或支鏈構型。The term "alkyl" as used herein means a monovalent saturated hydrocarbon group, which may be straight or branched chain or a combination thereof. Unless otherwise defined, these alkyl groups typically contain 1-12 carbon atoms. Representative alkyl groups include, for example, methyl (Me), ethyl (Et), n-propyl ((n-Pr) or (nPr)), isopropyl ((i-Pr) or (iPr)) , n-butyl ((n-Bu) or (nBu)), sec-butyl, isobutyl, tert-butyl ((t-Bu) or (tBu)), n-pentyl, n-hexyl, 2,2- Dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2-ethylbutyl, 2,2-dimethylpentyl, 2-propylpentyl, and the like. When a specific number of carbon atoms is used in a specific term, the number of carbon atoms is shown before the term. For example, the term " C1-3 alkyl" means an alkyl group having 1 to 3 carbon atoms, wherein the carbon atoms are in any chemically acceptable configuration, including straight or branched chain configurations.
本文使用的術語「鹵代烷基」是指含有1至12個碳原子的直鏈或支鏈烷基(如上面所提到)，其中這些基團中的一些或全部的氫原子被鹵素原子取代。C1-2 -鹵代烷基的實例包括氯甲基、溴甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基、氯氟甲基、二氯氟甲基、1-氯乙基、2-氟乙基、2,2-二氟乙基和2,2,2-三氟乙基。The term "haloalkyl" as used herein refers to straight or branched chain alkyl groups (as mentioned above) containing from 1 to 12 carbon atoms, wherein some or all of the hydrogen atoms in these groups are replaced by halogen atoms. Examples of C1-2 -haloalkyl include chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoro Methyl, 1-chloroethyl, 2-fluoroethyl, 2,2-difluoroethyl and 2,2,2-trifluoroethyl.
本文使用的術語「烷氧基」是指透過氧原子連接的烷基。術語「C1-2 -烷氧基」是如上面定義的透過氧原子連接的C1-2 -烷基。C1-3 -烷氧基的實例包括甲氧基、乙氧基、正丙氧基和1-甲基乙氧基(異丙氧基)。The term "alkoxy," as used herein, refers to an alkyl group attached through an oxygen atom. The term " C1-2 -alkoxy" is a C1-2 -alkyl group as defined above attached through an oxygen atom. Examples of C 1-3 -alkoxy groups include methoxy, ethoxy, n-propoxy and 1-methylethoxy (isopropoxy).
本文使用的術語「鹵代烷氧基」是指透過氧原子連接的鹵代烷基。C1-3 鹵代烷氧基的實例包括OCH2 F、OCHF2 、OCF3 、OCH2 Cl、OCHCl2 、OCCl3 、2-氟乙氧基、2-氯乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基、2-氯-2-氟乙氧基、2-氯-2,2-二氟乙氧基、2,2,2-三氯乙氧基和2-氟丙氧基。The term "haloalkoxy," as used herein, refers to a haloalkyl group attached through an oxygen atom. Examples of C 1-3 haloalkoxy include OCH 2 F, OCHF 2 , OCF 3 , OCH 2 Cl, OCHCl 2 , OCCl 3 , 2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoro Ethoxy, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2,2-difluoroethoxy, 2,2,2-trichloroethoxy oxy and 2-fluoropropoxy.
本文使用的術語「芳基」是指具有6至14個碳原子作為環成員的芳基。芳基是單、二或多環碳環的(即沒有雜原子作為環成員)環體系，其中一個或多個環是芳香族的。單環芳基的一個實例是苯基。在雙環中，兩個環可以進行縮合，即它們共用兩個鄰位C原子作為環成員。雙環芳基的一個實例是萘基。在多環芳基環中，三個或更多個環可以進行縮合。多環芳基的實例是茀基(9H-茀基)、菲基和蒽基。所述芳基的一個或多個氫可以獨立地被獨立地選自下面的取代基取代：鹵素、硝基、C1-3 烷基、C1-3 鹵代烷基、C1-3 烷氧基和C1-3 鹵代烷氧基。The term "aryl" as used herein refers to an aryl group having 6 to 14 carbon atoms as ring members. Aryl is a mono-, bi- or polycyclic carbocyclic (ie no heteroatoms as ring members) ring system in which one or more rings are aromatic. An example of a monocyclic aryl group is phenyl. In bicyclic rings, two rings can undergo condensation, ie they share two vicinal C atoms as ring members. An example of a bicyclic aryl group is naphthyl. In polycyclic aryl rings, three or more rings may be condensed. Examples of polycyclic aryl groups are fentanyl (9H-fentanyl), phenanthryl and anthracenyl. One or more hydrogens of the aryl group may be independently substituted with substituents independently selected from the group consisting of halogen, nitro, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 1-3 haloalkoxy.
本文使用的術語「芳基甲氧基」是如上面定義的芳基，其透過甲氧基與分子的其餘部分結合。芳基甲氧基的實例包括苄基氧基、9-茀基甲氧基、對硝基苄基氧基、2,4-二氯苄基氧基和5-苯並異噁唑基甲氧基。The term "arylmethoxy," as used herein, is an aryl group, as defined above, which is bound to the rest of the molecule through a methoxy group. Examples of arylmethoxy include benzyloxy, 9-intenylmethoxy, p-nitrobenzyloxy, 2,4-dichlorobenzyloxy, and 5-benzisoxazolylmethoxy base.
用於在式14化合物與式9化合物間形成醯胺鍵的合適的「耦合劑」可以選自N,N'-羰基二咪唑(CDI)、N,N'-二環己基碳二亞胺(DCC)、1-(3-二甲基氨基丙基)-3-乙基碳二亞胺鹽酸鹽(EDCI)、1-羥基-1,2,3-苯並三唑(HOBT)、苯並三唑-1-基氧基-三(二甲氨基)-鏻六氟磷酸鹽(BOP)、苯並三唑-1-基氧基-三吡咯烷基-鏻六氟磷酸鹽(PyBOP)、1-[雙(二甲氨基)-亞甲基]-1H-1,2,3-三唑並[4,5-b]吡啶鎓-3-氧化物六氟磷酸鹽(1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxi-de hexafluorophosphate)(HATU)、O-苯並三唑-N,N,N’,N'-四甲基脲-六氟磷酸酯(HBTU)、(2-(6-氯-1H-苯並三唑-1-基)-N,N,N’,N'-四甲基銨六氟磷酸鹽(HCTU)和O-苯並三唑-1-基-N,N,N’,N'-四甲基脲四氟硼酸酯(TBTU)。Suitable "coupling agents" for forming the amide bond between the compound of formula 14 and the compound of formula 9 can be selected from N,N'-carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide ( DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxy-1,2,3-benzotriazole (HOBT), benzene Triazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidinyl-phosphonium hexafluorophosphate (PyBOP) , 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (1-[bis (dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxi-de hexafluorophosphate)(HATU), O-benzotriazole-N,N,N', N'-tetramethylurea-hexafluorophosphate (HBTU), (2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylammonium Hexafluorophosphate (HCTU) and O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea tetrafluoroborate (TBTU).
本文使用的術語「甲醛同等物(formaldehyde equivalent)」是指甲醛或其化學同等物，如，但不限於三聚甲醛(metaformaldehyde)、低聚甲醛(paraformaldehyde)或聚甲醛(polyformaldehyde)。As used herein, the term "formaldehyde equivalent" refers to formaldehyde or a chemical equivalent thereof, such as, but not limited to, metaformaldehyde, paraformaldehyde, or polyformaldehyde.
本文使用的術語「非極性有機溶劑」包括脂肪族烴，如烷烴，例如戊烷、己烷、庚烷、辛烷，它們的混合物和技術混合物，例如石油醚；環脂肪族烴，如環烷烴，例如環己烷、環庚烷或環辛烷；氯代脂肪族烴，如鹵代烷烴，例如二氯甲烷、三氯甲烷、四氯甲烷、二氯乙烷或四氯乙烷，芳香族烴，如苯、甲苯、二甲苯、乙基苯、枯烯(異丙苯)、氯苯、鄰二氯苯或硝基苯，或開鏈醚，如二乙醚、二丙醚、甲基叔丁基醚或甲基異丁基醚。在某些實施方案中，非極性有機溶劑選自苯、甲苯、二甲苯、乙基苯、枯烯(異丙苯)、氯苯、鄰二氯苯和硝基苯。在其它的實施方案中，非極性有機溶劑選自甲苯、二甲苯和氯苯。The term "non-polar organic solvent" as used herein includes aliphatic hydrocarbons, such as alkanes, such as pentane, hexane, heptane, octane, mixtures thereof and technical mixtures, such as petroleum ether; cycloaliphatic hydrocarbons, such as cycloalkanes , such as cyclohexane, cycloheptane or cyclooctane; chlorinated aliphatic hydrocarbons, such as halogenated alkanes, such as dichloromethane, chloroform, tetrachloromethane, dichloroethane or tetrachloroethane, aromatic hydrocarbons , such as benzene, toluene, xylene, ethylbenzene, cumene (cumene), chlorobenzene, o-dichlorobenzene or nitrobenzene, or open-chain ethers such as diethyl ether, dipropyl ether, methyl tert-butyl ether ether or methyl isobutyl ether. In certain embodiments, the non-polar organic solvent is selected from the group consisting of benzene, toluene, xylene, ethylbenzene, cumene (cumene), chlorobenzene, ortho-dichlorobenzene, and nitrobenzene. In other embodiments, the non-polar organic solvent is selected from the group consisting of toluene, xylene, and chlorobenzene.
本文使用的術語「極性非質子溶劑」包括溶劑，其在用於反應的水/極性非質子溶劑的理想比例中是可與水混溶的。極性非質子溶劑是沒有質子可以離解的官能團的溶劑。「可溶混的」意指形成均質溶液。合適的極性非質子溶劑的實例是醯胺，如N,N-二甲基甲醯胺(DMF)和N,N-二甲基乙醯胺；亞碸，如二甲基亞碸(DMSO)；內醯胺類，如N-甲基吡咯烷酮(NMP)；環醚，如四氫呋喃、1,3-二噁烷和1,4-二噁烷；酮，如丙酮和甲基乙基酮；腈，如乙腈；內酯，如γ-丁內酯；硝基化合物，如硝基甲烷；脲類，如四甲基脲或二甲基丙烯脲(DMPU)；碸類，如環丁碸；和碳酸酯，如碳酸二甲酯或碳酸亞乙基酯。在某些實施方案中，極性非質子共溶劑是環醚，如四氫呋喃或1,4-二噁烷。The term "polar aprotic solvent" as used herein includes solvents that are miscible with water in the ideal ratio of water/polar aprotic solvent used in the reaction. Polar aprotic solvents are solvents that do not have functional groups from which protons can dissociate. "Miscible" means forming a homogeneous solution. Examples of suitable polar aprotic solvents are amides such as N,N-dimethylformamide (DMF) and N,N-dimethylacetamide; methylenes such as dimethylsulfoxide (DMSO) ; lactamides such as N-methylpyrrolidone (NMP); cyclic ethers such as tetrahydrofuran, 1,3-dioxane and 1,4-dioxane; ketones such as acetone and methyl ethyl ketone; nitriles , such as acetonitrile; lactones, such as gamma-butyrolactone; nitro compounds, such as nitromethane; ureas, such as tetramethylurea or dimethylpropylene urea (DMPU); Carbonates such as dimethyl carbonate or ethylene carbonate. In certain embodiments, the polar aprotic co-solvent is a cyclic ether, such as tetrahydrofuran or 1,4-dioxane.
本文使用的術語「極性質子溶劑」包括溶劑，如水、乙酸、甲酸、甲醇、乙醇、正丁醇、1-丁醇、2-丁醇、異丁醇、仲丁醇、叔丁醇、正丙醇、異丙醇、1,2-丙-二醇和甘油。The term "polar protic solvent" as used herein includes solvents such as water, acetic acid, formic acid, methanol, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-butanol, Propanol, isopropanol, 1,2-propane-diol and glycerol.
本文使用的術語「鹼」是指無機和有機鹼。合適的無機鹼可包括例如鹼金屬碳酸鹽，例如Li2 CO3 、Na2 CO3 、K2 CO3 或Cs2 CO3 ,，鹼土金屬(earth alkaline)碳酸鹽，例如MgCO3 或CaCO3 ，鹼金屬磷酸鹽，例如Li3 PO4 、Na3 PO4 、K3 PO4 或Cs3 PO4 ，鹼土金屬磷酸鹽，例如Mg3 (PO4 )2 或Ca3 (PO4 )2 ，鹼金屬磷酸氫鹽，例如Li2 HPO4 、Na2 HPO4 、K2 HPO4 或Cs2 HPO4 ，鹼土金屬磷酸氫鹽，例如MgHPO4 或CaHPO4 ，鹼金屬氫氧化物，LiOH、NaOH或KOH，和鹼土金屬氫氧化物，例如Mg(OH)2 或Ca(OH)2 。合適的有機鹼可以包括開鏈胺，如三甲胺、三乙胺、三丙胺、乙基二異丙胺等，或鹼性N-雜環，如嗎啉、吡啶、二甲基吡啶(lutidine)、DMAP、DABCO、DBU或DBN。 發明態樣The term "base" as used herein refers to both inorganic and organic bases. Suitable inorganic bases may include, for example, alkali metal carbonates such as Li 2 CO 3 , Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 , earth alkaline carbonates such as MgCO 3 or CaCO 3 , Alkali metal phosphates such as Li 3 PO 4 , Na 3 PO 4 , K 3 PO 4 or Cs 3 PO 4 , alkaline earth metal phosphates such as Mg 3 (PO 4 ) 2 or Ca 3 (PO 4 ) 2 , alkali metals Hydrogen phosphates such as Li 2 HPO 4 , Na 2 HPO 4 , K 2 HPO 4 or Cs 2 HPO 4 , alkaline earth metal hydrogen phosphates such as MgHPO 4 or CaHPO 4 , alkali metal hydroxides, LiOH, NaOH or KOH, and alkaline earth metal hydroxides such as Mg(OH) 2 or Ca(OH) 2 . Suitable organic bases may include open chain amines such as trimethylamine, triethylamine, tripropylamine, ethyldiisopropylamine, etc., or basic N-heterocycles such as morpholine, pyridine, lutidine, DMAP, DABCO, DBU or DBN. Invention aspect
第一態樣first aspect
在第一態樣，本發明提供了製備式13化合物或其鹽類的方法：
在一個實施方案中，所述反應在包含一種或多種選自下面的溶劑中進行：二氯甲烷、甲苯、四氫呋喃和2-甲基四氫呋喃。在另一個實施方案中，所述反應在非極性有機溶劑中進行。在另一個實施方案中，所述反應在甲苯中進行。在另一個實施方案中，所述反應在2-甲基四氫呋喃中進行。In one embodiment, the reaction is carried out in a solvent comprising one or more selected from the group consisting of dichloromethane, toluene, tetrahydrofuran, and 2-methyltetrahydrofuran. In another embodiment, the reaction is carried out in a non-polar organic solvent. In another embodiment, the reaction is carried out in toluene. In another embodiment, the reaction is carried out in 2-methyltetrahydrofuran.
在一個實施方案中，R1 、R2 、Ra 和Rb 是甲基或乙基。In one embodiment, R 1 , R 2 , Ra and R b are methyl or ethyl.
在另一個實施方案中，所述反應在鹼性條件下實施。在另外的實施方案中，將鹼加入到該反應中以產生鹼性條件。在另外的實施方案中，所述鹼是有機鹼。在另一個實施方案中，所述有機鹼是一種、兩種或更多種選自下面的鹼：DBU、DMAP、三乙胺、異丙胺、二丁胺、呱嗪、呱啶和嗎啉。在另一個實施方案中，所述堿是二甲基氨基吡啶(DMAP)。In another embodiment, the reaction is carried out under basic conditions. In other embodiments, a base is added to the reaction to create basic conditions. In additional embodiments, the base is an organic base. In another embodiment, the organic base is one, two or more bases selected from the group consisting of DBU, DMAP, triethylamine, isopropylamine, dibutylamine, oxazine, oxidine, and morpholine. In another embodiment, the phosphonium is dimethylaminopyridine (DMAP).
在另一個實施方案中，式1化合物和式12化合物和鹼性試劑(鹼)以1:1.05:1.5至1:2:3範圍的莫耳比進料。In another embodiment, the compound of formula 1 and the compound of formula 12 and the basic reagent (base) are fed in a molar ratio ranging from 1:1.05:1.5 to 1:2:3.
在另一個實施方案中，化合物1和乙醯氨基-(二甲氧基-磷醯基)-乙酸乙酯(1.1當量)可以懸浮在無水的二氯甲烷(DCM)中。向該攪拌溶液中可以加入DBU(2當量)。在加入過程中，內部溫度可以升至30-340 C，並通過TLC監測該反應進程(50:50 己烷:EtOAc)。反應不進一步進行後，可以加入4埃(Å)分子篩，並將混合物在室溫下攪拌過夜。蒸發溶劑，並在攪拌下將懸浮在MeOH和水中的殘留物加入。至少1至3小時後，將該混合物過濾，並將濾餅在攪拌下用MeOH:水(2:1)洗滌。在產物(化合物13，其中R1 是乙基且R2 是甲基)適合後續步驟使用之前，可能需要進一步純化以除去分子篩和其它的雜質。In another embodiment, Compound 1 and acetamido-(dimethoxy-phosphoronyl)-ethyl acetate (1.1 equiv) can be suspended in dry dichloromethane (DCM). To this stirred solution can be added DBU (2 equiv.). During the addition, the internal temperature was allowed to rise to 30-34 °C and the progress of the reaction was monitored by TLC (50:50 hexanes:EtOAc). After the reaction does not proceed further, 4 Angstrom (Å) molecular sieves can be added and the mixture is stirred at room temperature overnight. The solvent was evaporated and the residue suspended in MeOH and water was added with stirring. After at least 1 to 3 hours, the mixture was filtered and the filter cake was washed with MeOH:water (2:1) with stirring. Further purification to remove molecular sieves and other impurities may be required before the product (compound 13 , wherein R1 is ethyl and R2 is methyl ) is suitable for use in subsequent steps.
在另一個實施方案中，後處理(workup)模式如下：反應完成後，向反應中加入氯化銨水溶液，並將該反應混合物進行攪拌並洗滌；分離並除去水層，將有機層用飽和鹽水洗滌，然後濃縮；將甲醇/水加入到濃縮的溶液中並攪拌以結晶，並將沉澱的晶體進行過濾並乾燥以得到式13化合物。In another embodiment, the workup mode is as follows: after the reaction is completed, an aqueous ammonium chloride solution is added to the reaction, and the reaction mixture is stirred and washed; the aqueous layer is separated and removed, and the organic layer is washed with saturated brine Washed, then concentrated; methanol/water was added to the concentrated solution and stirred to crystallize, and the precipitated crystals were filtered and dried to give the compound of formula 13.
第二態樣second aspect
在第二態樣，本發明提供了製備式14化合物或其鹽類的方法：
在一個實施方案中，所述反應在溶劑中進行。在一個實施方案中，所述溶劑是極性非質子溶劑。在另外的實施方案中，所述溶劑是選自下面的一種、兩種或更多種：1,4-二噁烷、N-甲基吡咯烷酮、二甲基亞碸、二甲基乙醯胺和二甲基甲醯胺。在另外的實施方案中，所述溶劑是N-甲基吡咯烷酮。In one embodiment, the reaction is carried out in a solvent. In one embodiment, the solvent is a polar aprotic solvent. In further embodiments, the solvent is one, two or more selected from the group consisting of 1,4-dioxane, N-methylpyrrolidone, dimethylsulfene, dimethylacetamide and dimethylformamide. In additional embodiments, the solvent is N-methylpyrrolidone.
在另一個實施方案中，所述反應在酸性條件下實施。在另外的實施方案中，將酸加入到該反應中以產生酸性條件。在另外的實施方案中，所述酸是水性溶液，其中所述酸是選自下面的一種、兩種或更多種：鹽酸、硫酸和磷酸。在另外的實施方案中，所述酸是鹽酸的水性溶液。In another embodiment, the reaction is carried out under acidic conditions. In other embodiments, an acid is added to the reaction to create acidic conditions. In further embodiments, the acid is an aqueous solution, wherein the acid is one, two or more selected from the group consisting of hydrochloric acid, sulfuric acid, and phosphoric acid. In additional embodiments, the acid is an aqueous solution of hydrochloric acid.
在另一個實施方案中，式13化合物和酸性水性溶液以1:10至1:13範圍的莫耳比進料，並且所述酸性水性溶液的濃度在2 mol/L和6 mol/L之間。In another embodiment, the compound of formula 13 and the acidic aqueous solution are fed in a molar ratio ranging from 1:10 to 1:13, and the concentration of the acidic aqueous solution is between 2 mol/L and 6 mol/L .
在另一個實施方案中，後處理模式如下：反應完成後，降低溫度並加水，並攪拌至結晶；在過濾後獲得濕產物，然後將所述濕產物與甲醇/二氯甲烷一起漿化；在過濾和乾燥後獲得化合物14。In another embodiment, the work-up mode is as follows: after the reaction is complete, reduce the temperature and add water, and stir until crystallization; obtain a wet product after filtration, which is then slurried with methanol/dichloromethane; Compound 14 was obtained after filtration and drying.
第三態樣third aspect
在第三態樣，本發明提供了製備式15化合物或其鹽類的方法：
在一個實施方案中，所述反應在溶劑中進行，其中所述溶劑是一種、兩種或更多種選自下面的溶劑：二噁烷、N-甲基吡咯烷酮、二甲基亞碸、甲苯、二甲基甲醯胺和二甲基乙醯胺。在另一個實施方案中，所述溶劑是甲苯和二甲基乙醯胺的混合物。在另一個實施方案中，所述溶劑是極性非質子溶劑和非極性有機溶劑的混合物。In one embodiment, the reaction is carried out in a solvent, wherein the solvent is one, two or more solvents selected from the group consisting of dioxane, N-methylpyrrolidone, dimethylsulfoxide, toluene , dimethylformamide and dimethylacetamide. In another embodiment, the solvent is a mixture of toluene and dimethylacetamide. In another embodiment, the solvent is a mixture of a polar aprotic solvent and a non-polar organic solvent.
在另一個實施方案中，所述反應在鹼性條件下實施。在另外的實施方案中，所述鹼性反應條件是通過加入有機鹼創造的。在另外的實施方案中，所述有機鹼是選自下面的一種、兩種或更多種：三乙胺、異丙胺、二乙胺、正丁胺、DBU、DMAP和N,N-二異丙基乙基胺。在另一個實施方案中，所述有機鹼是異丙胺。In another embodiment, the reaction is carried out under basic conditions. In additional embodiments, the basic reaction conditions are created by the addition of an organic base. In further embodiments, the organic base is one, two or more selected from the group consisting of triethylamine, isopropylamine, diethylamine, n-butylamine, DBU, DMAP and N,N-diiso Propylethylamine. In another embodiment, the organic base is isopropylamine.
在該反應中使用的還原劑可以是任何還原劑，其適於還原在式14化合物和(S)-苯基丙基胺之間形成的亞胺，而基本上不與該化合物的其它部分發生反應。在一個實施方案中，所述還原劑可以是硼氫化物試劑，如硼氫化鈉、氰基硼氫化鈉、三乙醯氧基硼氫化鈉、三[2-(乙基己酸)]硼氫化鈉(sodium tris[2-(ethylhexanoic)]borohydride)等。在另一個實施方案中，所述還原劑可以原位形成。在另一個實施方案中，所述還原劑是三[2-(乙基己酸)]硼氫化鈉。在另一個實施方案中，所述還原劑是NaBH(OCORc )3 ，其中Rc 是C1 -C12 烷基，且較佳為C7 -C9 烷基。所述還原劑的莫耳質量可以在化合物14的莫耳質量的1到3倍之間，較佳為1.5到2倍之間。The reducing agent used in this reaction can be any reducing agent suitable for reducing the imine formed between the compound of formula 14 and (S)-phenylpropylamine without substantially interacting with the rest of the compound reaction. In one embodiment, the reducing agent may be a borohydride reagent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, tris[2-(ethylhexanoic acid)]borohydride Sodium (sodium tris[2-(ethylhexanoic)]borohydride) and so on. In another embodiment, the reducing agent may be formed in situ. In another embodiment, the reducing agent is sodium tris[2-(ethylhexanoic acid)]borohydride. In another embodiment, the reducing agent is NaBH(OCOR c ) 3 , wherein R c is C 1 -C 12 alkyl, and preferably C 7 -C 9 alkyl. The molar mass of the reducing agent may be between 1 and 3 times the molar mass of compound 14, preferably between 1.5 and 2 times.
在一個實施方案中，所述反應如下進行後處理：反應完成後，將部分溶劑通過濃縮除去，然後加入甲醇並攪拌至結晶。In one embodiment, the reaction is worked up as follows: After the reaction is complete, part of the solvent is removed by concentration, then methanol is added and stirred until crystallization.
第四態樣fourth aspect
在第四態樣，本發明提供了製備式8化合物或其鹽類的方法：
在一個實施方案中，所述反應形成式8化合物的鈉鹽。In one embodiment, the reaction forms the sodium salt of the compound of formula 8.
在一個實施方案中，所述反應溶劑是極性非質子溶劑和非極性有機溶劑的混合物。在另一個實施方案中，所述溶劑是選自下面的一種、兩種或更多種：甲苯、二甲苯、氯苯、乙酸乙酯、乙酸異丙酯、乙酸丙酯和乙酸丁酯。在另一個實施方案中，所述溶劑是氯苯和乙酸異丙酯的混合物。In one embodiment, the reaction solvent is a mixture of a polar aprotic solvent and a non-polar organic solvent. In another embodiment, the solvent is one, two or more selected from the group consisting of toluene, xylene, chlorobenzene, ethyl acetate, isopropyl acetate, propyl acetate and butyl acetate. In another embodiment, the solvent is a mixture of chlorobenzene and isopropyl acetate.
在另一個實施方案中，向該反應物中加入酸催化劑。在另外的實施方案中，所述酸催化劑是選自下面的一種、兩種或更多種：三氟乙酸、濃硫酸、鹽酸和三氟甲磺酸。在另一個實施方案中，所述酸催化劑是三氟甲磺酸。In another embodiment, an acid catalyst is added to the reactant. In further embodiments, the acid catalyst is one, two or more selected from the group consisting of trifluoroacetic acid, concentrated sulfuric acid, hydrochloric acid, and trifluoromethanesulfonic acid. In another embodiment, the acid catalyst is trifluoromethanesulfonic acid.
在另一個實施方案中，所述反應在20至50°C的溫度範圍內實施，並且較佳在30至40°C的範圍內。In another embodiment, the reaction is carried out at a temperature in the range of 20 to 50°C, and preferably in the range of 30 to 40°C.
在另一個實施方案中，後處理模式如下：降低溫度，加入1至4 mol/L的氫氧化鈉溶液，其重量為化合物15的8至11倍；攪拌並萃取後，分離有機層，然後用飽和鹽水洗滌；加入高沸點溶劑，然後通過攪拌和濃縮除去低沸點溶劑；停止濃縮直至剩餘的濃縮溶液約為化合物15重量的4倍；並將剩餘的濃縮溶液直接用在下一步反應中。所述高沸點溶劑是選自下面的一種、兩種或更多種：N,N-二甲基甲醯胺，N,N-二甲基乙醯胺和二甲基亞碸，並且較佳為N,N-二甲基乙醯胺。In another embodiment, the post-treatment mode is as follows: reduce the temperature, add 1 to 4 mol/L sodium hydroxide solution, the weight of which is 8 to 11 times that of compound 15; after stirring and extraction, separate the organic layer, and then use Wash with saturated brine; add high boiling point solvent, then remove low boiling point solvent by stirring and concentration; stop concentration until the remaining concentrated solution is about 4 times the weight of compound 15; and use the remaining concentrated solution directly in the next reaction. The high boiling point solvent is one, two or more selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide and dimethylsulfoxide, and preferably It is N,N-dimethylacetamide.
第五態樣fifth aspect
在第五態樣，本發明提供了製備式10化合物或其鹽類的方法：
在一個實施方案中，所述反應溶劑是極性非質子溶劑。在另一個實施方案中，所述反應溶劑是選自下面的一種、兩種或更多種：N,N-二甲基甲醯胺、N,N-二甲基乙醯胺和二甲基亞碸。在另一個實施方案中，所述反應溶劑是N,N-二甲基乙醯胺。In one embodiment, the reaction solvent is a polar aprotic solvent. In another embodiment, the reaction solvent is one, two or more selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, and dimethylformamide asian. In another embodiment, the reaction solvent is N,N-dimethylacetamide.
在另一個實施方案中，M是鹼金屬。在另外的實施方案中，M是鈉。In another embodiment, M is an alkali metal. In additional embodiments, M is sodium.
在另一個實施方案中，所述反應在10至40°C的溫度範圍內實施，並且較佳在20至30°C的範圍內實施。In another embodiment, the reaction is carried out at a temperature in the range of 10 to 40°C, and preferably in the range of 20 to 30°C.
在另一個實施方案中，向該反應物中加入耦合劑。在另一個實施方案中，所述耦合劑選自HATU、HBTU、HCTU、PyBOP和TBTU。在另一個實施方案中，所述耦合劑是PyBOP。In another embodiment, a coupling agent is added to the reactant. In another embodiment, the coupling agent is selected from the group consisting of HATU, HBTU, HCTU, PyBOP and TBTU. In another embodiment, the coupling agent is PyBOP.
在另一個實施方案中，所述反應在鹼性條件下進行。在另一個實施方案中，所述鹼性反應條件是通過將鹼加入到該反應中實現的。在一個實施方案中，所述鹼是有機鹼。在另外的實施方案中，所述鹼選自三乙胺、N-甲基嗎啉、二異丙基乙基胺和4-甲基氨基吡啶。在另一個實施方案中，所述鹼是N-甲基嗎啉。In another embodiment, the reaction is carried out under basic conditions. In another embodiment, the basic reaction conditions are achieved by adding a base to the reaction. In one embodiment, the base is an organic base. In further embodiments, the base is selected from triethylamine, N-methylmorpholine, diisopropylethylamine, and 4-methylaminopyridine. In another embodiment, the base is N-methylmorpholine.
在另一個實施方案中，化合物8-M和耦合劑以1:1.1至1:3範圍的莫耳比進料。在另一個實施方案中，化合物8-M、化合物9和有機鹼以1:1.05:1至1:1.1:3範圍的莫耳比進料。In another embodiment, Compound 8-M and the coupling agent are fed in a molar ratio ranging from 1:1.1 to 1:3. In another embodiment, Compound 8-M, Compound 9, and the organic base are fed in a molar ratio ranging from 1:1.05:1 to 1:1.1:3.
在另一個實施方案中，後處理模式如下：反應完成後，在攪拌下加入乙酸乙酯和水進行萃取，分離並除去水層，將有機層傾倒入用在下一步的反應溶劑中，然後濃縮直至剩餘的濃縮溶液按重量計約為化合物8-M的2倍；並將剩餘的濃縮溶液直接用在下一步反應中而不進行分離。In another embodiment, the work-up mode is as follows: after the reaction is complete, add ethyl acetate and water for extraction with stirring, separate and remove the aqueous layer, pour the organic layer into the reaction solvent used in the next step, and then concentrate until The remaining concentrated solution was about 2 times by weight of compound 8-M; the remaining concentrated solution was directly used in the next reaction without isolation.
第六態樣sixth aspect
在第六態樣，本發明提供了製備OAD2的單HCl鹽(式11化合物)的方法，其中所述方法包括第一步：水解式10化合物的甲基酯
在一個實施方案中，所述反應溶劑是極性非質子溶劑。在另一個實施方案中，所述反應溶劑選自2-甲基四氫呋喃、四氫呋喃、1,4-二噁烷、丙酮和乙腈，並且較佳是四氫呋喃。在另一個實施方案中，所述溶劑的重量是OAD2的4至8倍。In one embodiment, the reaction solvent is a polar aprotic solvent. In another embodiment, the reaction solvent is selected from 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, acetone and acetonitrile, and is preferably tetrahydrofuran. In another embodiment, the solvent is 4 to 8 times the weight of OAD2.
在另一個實施方案中，所述反應在10至40°C的溫度範圍內實施，並且較佳在15至25°C的範圍內實施。In another embodiment, the reaction is carried out in a temperature range of 10 to 40°C, and preferably in a range of 15 to 25°C.
在一個實施方案中，向該反應物中加入鹼性溶液。在另外的實施方案中，所述鹼性溶液是2至4 mol/L的氫氧化鈉溶液，並且化合物10和氫氧化鈉以1:4至1:6範圍的莫耳比進料。In one embodiment, an alkaline solution is added to the reactants. In additional embodiments, the alkaline solution is a 2 to 4 mol/L sodium hydroxide solution, and Compound 10 and sodium hydroxide are fed in a molar ratio ranging from 1 :4 to 1 :6.
在另一個實施方案中，加入1至2mol/L的鹽酸溶液的過程；並將pH調節至1至4的範圍，較佳至2至3的範圍。In another embodiment, the process of adding 1 to 2 mol/L hydrochloric acid solution; and adjusting the pH to the range of 1 to 4, preferably to the range of 2 to 3.
在另一個實施方案中，後處理模式如下：將pH調節至1至4之間後，將反應混合物攪拌至結晶或靜置結晶，並且較佳為靜置結晶。In another embodiment, the work-up mode is as follows: After adjusting the pH to between 1 and 4, the reaction mixture is stirred until crystallisation or standing crystallisation, and preferably standing crystallisation.
第七態樣seventh aspect
在第七態樣，本發明提供了製備OAD2的雙HCl鹽的方法，其中所述方法包括將OAD2的單HCl鹽(式11化合物)與HCl反應，以製備OAD2的雙HCl鹽。In a seventh aspect, the present invention provides a method of preparing a bis-HCl salt of OAD2, wherein the method comprises reacting a mono-HCl salt of OAD2 (a compound of formula 11) with HCl to prepare a bis-HCl salt of OAD2.
在一個實施方案中，所述反應在溶劑混合物中進行，所述溶劑混合物包含水和極性非質子溶劑。在另一個實施方案中，所述反應在溶劑混合物中進行，所述溶劑混合物包含水和選自乙酸、四氫呋喃和丙酮的溶劑。在另一個實施方案中，所述反應在溶劑混合物中進行，所述溶劑混合物包含水和四氫呋喃，並且所述反應溶劑的重量是OAD2的單HCl鹽的15至20倍。In one embodiment, the reaction is carried out in a solvent mixture comprising water and a polar aprotic solvent. In another embodiment, the reaction is carried out in a solvent mixture comprising water and a solvent selected from the group consisting of acetic acid, tetrahydrofuran and acetone. In another embodiment, the reaction is carried out in a solvent mixture comprising water and tetrahydrofuran, and the weight of the reaction solvent is 15 to 20 times the weight of the mono-HCl salt of OAD2.
在另一個實施方案中，在反應過程中，首先加入鹽酸溶液A並攪拌，隨後加入水並進一步攪拌，然後加入鹽酸溶液B並攪拌至結晶。鹽酸溶液A的重量是OAD2的單HCl鹽的2至3倍，並且鹽酸溶液B的重量是化合物OAD2的單HCl鹽的6至8倍。鹽酸溶液A和B的濃度是3至6mol/L，較佳為4至5mol/L。In another embodiment, during the reaction, hydrochloric acid solution A is first added and stirred, then water is added and further stirred, and then hydrochloric acid solution B is added and stirred until crystallization. The weight of hydrochloric acid solution A was 2 to 3 times that of the mono-HCl salt of OAD2, and the weight of hydrochloric acid solution B was 6 to 8 times that of the mono-HCl salt of compound OAD2. The concentrations of the hydrochloric acid solutions A and B are 3 to 6 mol/L, preferably 4 to 5 mol/L.
根據本發明，具體的製備方法可以包括如下面的方案2中所示的態樣1至7中的一個或多個步驟。
第八態樣eighth aspect
在第八態樣，本發明提供了中間體式13化合物和式14化合物。在一個實施方案中，本發明提供了式13化合物或其鹽類：
在另一個實施方案中，本發明提供了式14化合物或其鹽類：
本發明可以實現下面的有益效果：與現有技術方法相比，本發明用於製備OAD2二鹽酸鹽的方法具有較少的步驟，不需要通過管柱層析進行分離和純化，並且適合於工業規模生產。此外，在本發明的方法中，由化合物15製備OAD2的單HCl鹽的步驟可以以連續進料模式進行，可以不需要純化過程；簡化後處理並最大限度地減少產品損失；固體產物可以通過酸性和鹼性的成鹽模式從某種溶劑中沉澱出來，來實現純化效果，並且同時獲得高純度的OAD2單HCl鹽，然後通過進一步的成鹽步驟獲得目標化合物OAD2二HCl鹽。本發明的製備方法，從化合物1到最終產物化合物OAD2二鹽酸鹽，可以具有超過35%的總產率，並且最終產物的純度可以超過98%。與現有技術相比，本發明方法可以具有明顯改善的產率，並適用於大規模工業生產。本方法的某些實施方案已經達到50kg的批量並且展示出良好的製程穩定性和可控的產品品質。 實施例The present invention can achieve the following beneficial effects: compared with the prior art method, the method for preparing OAD2 dihydrochloride has fewer steps, does not require separation and purification by column chromatography, and is suitable for industrial mass production. In addition, in the method of the present invention, the step of preparing the mono-HCl salt of OAD2 from compound 15 can be carried out in a continuous feeding mode, and no purification process can be required; the post-processing is simplified and the product loss is minimized; the solid product can be passed through the acid And the basic salt-forming mode is precipitated from a certain solvent to achieve the purification effect, and at the same time obtain high-purity OAD2 mono-HCl salt, and then obtain the target compound OAD2 di-HCl salt through a further salt-forming step. The preparation method of the present invention, from compound 1 to the final product compound OAD2 dihydrochloride, can have an overall yield of more than 35%, and the purity of the final product can exceed 98%. Compared with the prior art, the method of the present invention can have a significantly improved yield and is suitable for large-scale industrial production. Certain embodiments of the present method have reached batch sizes of 50 kg and exhibit good process stability and controllable product quality. Example
本發明將通過將下面的特定的實施例組合來進一步進行說明。下面的實施例是用於解釋本發明的方法及其核心概念，並且對於本領域技術人員而言，不偏離本發明概念的任何可能的變化或替代落在本發明的保護範圍內。在下面的實施例中，在沒有指出實驗方法的具體條件的情況下，它們通常是常規條件，或者是原材料或商品製造商推薦的那些條件；並且沒有指出來源的溶劑通常是市售的常規溶劑。化合物1、12和9可以根據描述在CN102378574B和WO2007093013 A1中的方法進行製備，將它們的全文併入本文中作為參考。The invention will be further illustrated by combining the following specific embodiments. The following embodiments are used to explain the method of the present invention and its core concept, and for those skilled in the art, any possible changes or substitutions without departing from the concept of the present invention fall within the protection scope of the present invention. In the following examples, where specific conditions of the experimental methods are not indicated, they are generally conventional conditions, or those recommended by the manufacturers of raw materials or commercial products; and solvents that do not indicate sources are generally commercially available conventional solvents . Compounds 1, 12 and 9 can be prepared according to the methods described in CN102378574B and WO2007093013 A1, which are hereby incorporated by reference in their entirety.
實施例1：製備化合物13 (其中R1 是乙基且R2 是甲基)的方法Example 1 : Method for the preparation of compound 13 wherein R1 is ethyl and R2 is methyl
向化合物1(30kg)的DCM溶液中加入乙醯氨基-(二甲氧基-磷醯基)-乙酸乙酯(19.2kg)。將該混合物冷卻至16.8 °C並在2小時內加入DBU(22.17kg)，保持內部溫度低於34°C。將反應混合物在25 °C-30 °C攪拌過夜。加入飽和NH4 Cl水溶液(250 L)，將該混合物攪拌1.5小時，然後將其靜置1小時。分離有機層並加入DCM(199.3kg)，並將該混合物攪拌1小時。加入鹽水(300L)，將該混合物攪拌30分鐘，靜置過夜。分離有機層。將水相用DCM(150.4kg)攪拌1小時，分離有機層。過濾合併的有機相，將濾液濃縮至170L的體積。加入MeOH(199.4kg)並將該混合物濃縮至165L體積。加入MeOH(199.7kg)，將該混合物濃縮至180L體積。加入MeOH(68.4kg)和水(150.2kg)並將該混合物在室溫下攪拌過夜並過濾。將過濾後的固體用MeOH(159.6kg)和水(100.0kg)處理並攪拌過夜。To a solution of compound 1 (30 kg) in DCM was added acetamido-(dimethoxy-phosphoronyl)-ethyl acetate (19.2 kg). The mixture was cooled to 16.8°C and DBU (22.17kg) was added over 2 hours, keeping the internal temperature below 34°C. The reaction mixture was stirred at 25°C-30°C overnight. Saturated aqueous NH4Cl (250 L) was added and the mixture was stirred for 1.5 hours, then allowed to stand for 1 hour. The organic layer was separated and DCM (199.3 kg) was added and the mixture was stirred for 1 hour. Brine (300 L) was added and the mixture was stirred for 30 minutes and allowed to stand overnight. The organic layer was separated. The aqueous phase was stirred with DCM (150.4 kg) for 1 hour and the organic layer was separated. The combined organic phases were filtered and the filtrate was concentrated to a volume of 170L. MeOH (199.4 kg) was added and the mixture was concentrated to a volume of 165 L. MeOH (199.7 kg) was added and the mixture was concentrated to a volume of 180 L. MeOH (68.4 kg) and water (150.2 kg) were added and the mixture was stirred at room temperature overnight and filtered. The filtered solid was treated with MeOH (159.6 kg) and water (100.0 kg) and stirred overnight.
將該混合物的約一半進行過濾，並將收集的固體用水(10.0kg)和MeOH(16.0kg)洗滌。乾燥固體以獲得14.18kg的作為灰色固體的13。About half of the mixture was filtered and the collected solids were washed with water (10.0 kg) and MeOH (16.0 kg). The solid was dried to obtain 14.18 kg of 13 as a grey solid.
將上面提到的混合物剩下的一半進行過濾，並將收集的固體用水(15.0kg)和MeOH(24.0kg)洗滌。乾燥固體以獲得19.45kg的13，為灰色固體，總產率33.63kg。The remaining half of the above-mentioned mixture was filtered and the collected solids were washed with water (15.0 kg) and MeOH (24.0 kg). The solid was dried to give 19.45 kg of 13 as a grey solid in an overall yield of 33.63 kg.
實施例2：製備化合物14
將化合物13(31.3kg)(其中R1 是乙基且R2 是甲基)用二噁烷(242.8kg)處理並在環境溫度下攪拌。將混合物用6N鹽酸(由58.7kg水和70.4kg濃HCl水溶液製備)處理。將該混合物在攪拌下加熱回流(84-94.3 °C)19.5小時。將該混合物冷卻至25 °C並用水(782.5kg)處理。在20 °C攪拌1.5小時後過濾該混合物，並將收集的固體用30kg的水洗滌兩次。在攪拌下，將該固體在17-19 °C用水(300 kg)研磨1小時。通過過濾收集固體，並將收集的固體用30kg的水洗滌兩次。在攪拌下，將該固體在20 °C用86.7kg甲醇研磨2小時。通過過濾收集固體並用12.4kg甲醇洗滌。收集固體並在減壓下於39 °C進行乾燥。在攪拌下，將該固體在20 °C用二氯甲烷(165.9 kg)研磨2小時。通過過濾收集固體，用20.8kg二氯甲烷洗滌，並在減壓下於40 °C進行乾燥，以獲得20.76kg化合物14，其作為米色/灰白色固體。Compound 13 (31.3 kg) (wherein R1 is ethyl and R2 is methyl ) was treated with dioxane (242.8 kg) and stirred at ambient temperature. The mixture was treated with 6N hydrochloric acid (prepared from 58.7 kg of water and 70.4 kg of concentrated aqueous HCl). The mixture was heated to reflux (84-94.3 °C) with stirring for 19.5 hours. The mixture was cooled to 25 °C and treated with water (782.5 kg). After stirring for 1.5 hours at 20 °C the mixture was filtered and the collected solid was washed twice with 30 kg of water. With stirring, the solid was triturated with water (300 kg) at 17-19 °C for 1 hour. The solid was collected by filtration, and the collected solid was washed twice with 30 kg of water. With stirring, the solid was triturated with 86.7 kg of methanol at 20°C for 2 hours. The solid was collected by filtration and washed with 12.4 kg methanol. The solids were collected and dried under reduced pressure at 39°C. With stirring, the solid was triturated with dichloromethane (165.9 kg) at 20 °C for 2 hours. The solid was collected by filtration, washed with 20.8 kg of dichloromethane, and dried under reduced pressure at 40 °C to obtain 20.76 kg of compound 14 as a beige/off-white solid.
實施例3：製備化合物15
向反應容器中加入無水二噁烷(2.4L)、硼氫化鈉(278 g)和甲苯(2.4L)。將該混合物在25°C攪拌15-20分鐘。將該混合物冷卻至-7°C，並在90分鐘內加入2-乙基己酸(1.56L)，同時保持溫度在-5±2 °C。溫度升至10 °C以引發放熱反應，然後應用外部冷卻使內部溫度保持在15°C。將該反應混合物在15 °C攪拌18小時。還原劑的溶液無需進一步修飾即用於下一步。Anhydrous dioxane (2.4 L), sodium borohydride (278 g) and toluene (2.4 L) were added to the reaction vessel. The mixture was stirred at 25°C for 15-20 minutes. The mixture was cooled to -7°C and 2-ethylhexanoic acid (1.56 L) was added over 90 minutes while maintaining the temperature at -5±2°C. The temperature was raised to 10 °C to initiate an exothermic reaction, then external cooling was applied to maintain the internal temperature at 15 °C. The reaction mixture was stirred at 15°C for 18 hours. The reducing agent solution was used in the next step without further modification.
將甲苯(22.0L)和14(2.2kg)合併，向攪拌的懸浮液中加入三正丁胺(1.22L)，同時溫度保持低於25 °C。繼續在25 °C攪拌30分鐘直到所有的起始材料溶解。向該混合物中加入(S)-1-苯基丙-1-胺(810mL)，並將該混合物在25 °C攪拌1.5小時。將該混合物冷卻至10 °C，並保持溫度低於15 °C，逐滴加入還原劑(上面所製備)。將獲得的混合物在15 °C攪拌18小時。透過加入MeOH(600mL)淬滅該反應混合物並將混合物在25 °C攪拌1小時。將淬滅的反應混合物濃縮至乾燥，並將殘留物用DMF(8.1L)處理。將懸浮液在75-80 °C加熱30分鐘，將澄清溶液冷卻至25 °C並結晶樣品15(5g)。將該混合物冷卻至15 °C並攪拌30分鐘。通過過濾收集固體產物，並用2L的甲醇洗滌三次。乾燥產物以獲得1.98kg化合物15。Toluene (22.0 L) and 14 (2.2 kg) were combined and tri-n-butylamine (1.22 L) was added to the stirred suspension while maintaining the temperature below 25 °C. Continue stirring at 25°C for 30 minutes until all starting material is dissolved. To the mixture was added (S)-1-phenylpropan-1-amine (810 mL), and the mixture was stirred at 25 °C for 1.5 hours. The mixture was cooled to 10°C, keeping the temperature below 15°C, and the reducing agent (prepared above) was added dropwise. The obtained mixture was stirred at 15°C for 18 hours. The reaction mixture was quenched by adding MeOH (600 mL) and the mixture was stirred at 25 °C for 1 hour. The quenched reaction mixture was concentrated to dryness and the residue was treated with DMF (8.1 L). The suspension was heated at 75-80 °C for 30 minutes, the clear solution was cooled to 25 °C and sample 15 (5 g) was crystallized. The mixture was cooled to 15°C and stirred for 30 minutes. The solid product was collected by filtration and washed three times with 2 L of methanol. The product was dried to obtain 1.98 kg of compound 15.
實施例4A：製備化合物8-M (其中M是Na)
將二噁烷(1.93L)、TFA(6.43L)、甲苯(10L)和低聚甲醛(324g，10.8mol)混合並冷卻至27o C。將化合物15(1606g，2.713mol)和額外的甲苯(7.4L)一起加入。將該反應混合物在27o C攪拌20小時直至反應完成。將該混合物冷卻至22o C並用EtOAc(22L)稀釋，並用鹽水(20L)洗滌。將鹽水(8L)加入到有機層中，並用2M碳酸鈉將該混合物的pH調節至6.5(在3小時內加入19L)。分離有機層和水層，並用鹽水(15L)洗滌有機層。將有機層用硫酸鈉乾燥，通過矽藻土過濾並在減壓下濃縮。將殘留物溶於10L EtOAc中並與飽和碳酸鈉(10L)一起攪拌15分鐘。加入鹽水(10L)，並將該混合物攪拌10分鐘。分離有機層和水層，並通過硫酸鈉墊過濾有機層。用EtOAc洗滌該墊。將甲基叔丁基醚(MTBE)(110L)加入到濾液中並攪拌1小時。將獲得的固體在重力下過濾，並將收集的固體用MTBE(2L)洗滌。然後施加真空以除去溶劑，並將材料空氣乾燥過夜。將獲得的固體用攪拌旋轉蒸發儀乾燥6小時以得到1406g產物8-M。Dioxane (1.93 L), TFA (6.43 L), toluene (10 L) and paraformaldehyde (324 g, 10.8 mol) were combined and cooled to 27 ° C. Compound 15 (1606 g, 2.713 mol) was added along with additional toluene (7.4 L). The reaction mixture was stirred at 27 ° C for 20 hours until the reaction was complete. The mixture was cooled to 22 ° C and diluted with EtOAc (22 L) and washed with brine (20 L). Brine (8 L) was added to the organic layer and the pH of the mixture was adjusted to 6.5 with 2M sodium carbonate (19 L was added over 3 hours). The organic and aqueous layers were separated, and the organic layer was washed with brine (15 L). The organic layer was dried over sodium sulfate, filtered through celite and concentrated under reduced pressure. The residue was dissolved in 10 L of EtOAc and stirred with saturated sodium carbonate (10 L) for 15 minutes. Brine (10 L) was added and the mixture was stirred for 10 minutes. The organic and aqueous layers were separated, and the organic layer was filtered through a pad of sodium sulfate. The pad was washed with EtOAc. Methyl tert-butyl ether (MTBE) (110 L) was added to the filtrate and stirred for 1 hour. The obtained solid was filtered under gravity and the collected solid was washed with MTBE (2 L). A vacuum was then applied to remove the solvent and the material was air dried overnight. The obtained solid was dried on a stirred rotary evaporator for 6 hours to obtain 1406 g of product 8-M.
實施例4B：替代性製備化合物8-M (其中M是Na)Example 4B: Alternative Preparation of Compound 8-M (wherein M is Na)
將低聚甲醛(1176.0g)、TFA(26.0kg)、甲苯(48.4kg)和iPrOAc(12.1kg)混合。將該混合物的溫度調節至22.0 °C並將化合物15(5.9kg)與額外的6.0kg甲苯一起加入。將該混合物在25.7-30.8 °C攪拌約3.5小時。加入乙酸異丙酯(10.2kg)，並將獲得的混合物冷卻至5.9 °C。在26分鐘內加入4N NaOH(68kg)溶液，同時保持溫度低於25 °C。將該混合物的溫度調節至20.4°C，並將獲得的混合物在20.4-21.1°C攪拌10分鐘。分離各層，並將有機層用鹽水(2×14.6kg)洗滌。將有機層用DMF(10.8kg)稀釋，並將混合物在減壓下濃縮至12L體積。加入DMF(10.8kg)，並將該混合物在22.4-25.0 °C攪拌10分鐘。將8-M的DMF溶液用作實施例5B中的起始材料。Paraformaldehyde (1176.0 g), TFA (26.0 kg), toluene (48.4 kg) and iPrOAc (12.1 kg) were mixed. The temperature of the mixture was adjusted to 22.0 °C and compound 15 (5.9 kg) was added along with an additional 6.0 kg of toluene. The mixture was stirred at 25.7-30.8 °C for about 3.5 hours. Isopropyl acetate (10.2 kg) was added and the resulting mixture was cooled to 5.9 °C. 4N NaOH (68 kg) solution was added over 26 minutes while keeping the temperature below 25°C. The temperature of the mixture was adjusted to 20.4°C, and the obtained mixture was stirred at 20.4-21.1°C for 10 minutes. The layers were separated and the organic layer was washed with brine (2 x 14.6 kg). The organic layer was diluted with DMF (10.8 kg) and the mixture was concentrated under reduced pressure to a volume of 12 L. DMF (10.8 kg) was added and the mixture was stirred at 22.4-25.0 °C for 10 minutes. An 8-M solution in DMF was used as the starting material in Example 5B.
實施例5A：製備化合物10
在氮氣下，將化合物9((S)-2-氨基-3-[4-(2,3-二甲基-吡啶-4-基)-苯基-]-丙酸甲酯)(702.4g)溶於DMF(4.75升)，並將溫度調節至20o C。加入化合物8-M(1406g，2.246mol)、HBTU(937g，2.47mol)和DMF(2.75L)。加入NMM(4-甲基嗎啉)(493ml)，並將溫度升至28o C。將該混合物立即升至23-25o C並攪拌1小時。將混合物傾倒入劇烈攪拌的水(35L)中，並將獲得的懸浮液攪拌1小時。過濾固體並用水(10L)和己烷(10L)洗滌。將固體溶解在EtOAc(12L)中並用鹽水洗滌。將有機層用硫酸鈉乾燥，過濾並濃縮。將獲得的固體溶解在MTBE-DCM(3.1L，30:1)中，並使用MTBE作為洗脫劑在矽膠(6kg)上進行層析以得到化合物10(1851g)。Under nitrogen, compound 9 ((S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl-]-propionic acid methyl ester) (702.4 g ) was dissolved in DMF (4.75 L) and the temperature was adjusted to 20 ° C. Compound 8-M (1406 g, 2.246 mol), HBTU (937 g, 2.47 mol) and DMF (2.75 L) were added. NMM (4-methylmorpholine) (493ml) was added and the temperature was raised to 28 ° C. The mixture was immediately brought to 23-25 ° C and stirred for 1 hour. The mixture was poured into vigorously stirred water (35 L) and the resulting suspension was stirred for 1 hour. The solids were filtered and washed with water (10L) and hexanes (10L). The solid was dissolved in EtOAc (12 L) and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The obtained solid was dissolved in MTBE-DCM (3.1 L, 30:1) and chromatographed on silica gel (6 kg) using MTBE as eluent to give compound 10 (1851 g).
實施例5B：替代性製備化合物10Example 5B: Alternative Preparation of Compound 10
將化合物9(3.1kg)在8L DMF中的溶液用4-甲基嗎啉(2001.2g)處理。將所述在DMF中的化合物8-M溶液(來自實施例4B)與額外的DMF(3.5kg)一起加入。將該混合物的溫度調節至0 °C。加入HBTU(4.1 kg)，同時保持溫度低於15 °C。將該混合物溫熱至17.9o C並在17.9o C至22.6 °C攪拌3小時。將該反應混合物用EtOAc(42.1kg)稀釋，並將溫度調節至12.3 °C。加入水(69.6kg)並將獲得的混合物在19.1 °C至20.4 °C攪拌30分鐘。將分離的有機層在減壓下濃縮至6L體積。加入2-甲基四氫呋喃(9.9kg兩份)，並將該混合物在減壓下濃縮至6L體積。將獲得的化合物10的溶液保持在-10 ± 5 °C並在下一步實施例6中使用。A solution of compound 9 (3.1 kg) in 8 L DMF was treated with 4-methylmorpholine (2001.2 g). The solution of Compound 8-M in DMF (from Example 4B) was added with additional DMF (3.5 kg). The temperature of the mixture was adjusted to 0 °C. HBTU (4.1 kg) was added while keeping the temperature below 15 °C. The mixture was warmed to 17.9 ° C and stirred at 17.9 ° C to 22.6°C for 3 hours. The reaction mixture was diluted with EtOAc (42.1 kg) and the temperature was adjusted to 12.3 °C. Water (69.6 kg) was added and the resulting mixture was stirred at 19.1°C to 20.4°C for 30 minutes. The separated organic layer was concentrated under reduced pressure to a volume of 6 L. 2-Methyltetrahydrofuran (9.9 kg in two portions) was added and the mixture was concentrated under reduced pressure to a volume of 6 L. The obtained solution of compound 10 was kept at -10±5°C and used in the next step Example 6.
實施例6：製備OAD2二鹽酸鹽。
將來自實施例5B的化合物10的溶液用2-甲基四氫呋喃(29.9kg)稀釋。將該混合物溫熱至17.9 °C並在17.9-21.3 °C攪拌1小時。將該混合物冷卻至9.5 °C。加入2N NaOH(由NaOH 1568.9g，水19.4kg製備)，同時保持溫度低於20 °C。使混合物達到15.3 °C並在15.3-22.9 °C之間保持21小時。將該反應混合物冷卻至4.6 °C並用1N HCl將該混合物的pH調節至3.94。將反應混合物的溫度調節至8.8 °C。將該混合物在5.7-8.8 °C攪拌2.5小時，這導致漿液的形成。將該漿液溫熱至16.5 °C並在16.5-18.7 °C攪拌1小時。通過過濾收集固體，然後用水(5.8kg)和2-甲基四氫呋喃(5.1kg)洗滌。將固體產物在減壓下於39o C進行乾燥以獲得6.4kg粗制的OAD2-HCl，其作為白色固體。The solution of compound 10 from Example 5B was diluted with 2-methyltetrahydrofuran (29.9 kg). The mixture was warmed to 17.9 °C and stirred at 17.9-21.3 °C for 1 hour. The mixture was cooled to 9.5 °C. 2N NaOH (prepared from NaOH 1568.9g, water 19.4kg) was added while keeping the temperature below 20°C. The mixture was brought to 15.3 °C and held between 15.3-22.9 °C for 21 hours. The reaction mixture was cooled to 4.6 °C and the pH of the mixture was adjusted to 3.94 with 1 N HCl. The temperature of the reaction mixture was adjusted to 8.8 °C. The mixture was stirred at 5.7-8.8 °C for 2.5 hours, which resulted in the formation of a slurry. The slurry was warmed to 16.5 °C and stirred at 16.5-18.7 °C for 1 hour. The solid was collected by filtration, then washed with water (5.8 kg) and 2-methyltetrahydrofuran (5.1 kg). The solid product was dried under reduced pressure at 39 ° C to obtain 6.4 kg of crude OAD2-HCl as a white solid.
合併粗制的OAD2-HCl(6.4kg)、2-甲基四氫呋喃(110.2kg)和水(12.8kg)。將該混合物加熱至55.0 °C並在55.0-65.0°C攪拌2小時。在1h內將該混合物冷卻至25.0 °C，並在19.8-25.0 °C攪拌1小時。過濾固體，用2-甲基四氫呋喃(4.1kg)洗滌並在減壓下於39 °C進行乾燥以獲得4.2kg OAD2-HCl，其作為白色固體。Combine crude OAD2-HCl (6.4 kg), 2-methyltetrahydrofuran (110.2 kg) and water (12.8 kg). The mixture was heated to 55.0°C and stirred at 55.0-65.0°C for 2 hours. The mixture was cooled to 25.0 °C over 1 h and stirred at 19.8-25.0 °C for 1 h. The solid was filtered, washed with 2-methyltetrahydrofuran (4.1 kg) and dried under reduced pressure at 39 °C to obtain 4.2 kg of OAD2-HCl as a white solid.
將OAD2-HCl(4.1kg)用AcOH(8.9kg)處理，將該混合物的溫度調節至19.7 °C，並將該混合物在19.4-19.7 °C攪拌30分鐘。在10分鐘內加入5N HCl(由水5.0kg，37% HCl 4.2kg製備)，同時保持溫度低於25 °C。將該混合物在19.1-21.2 °C攪拌1小時。在1小時內加入水(84.0kg)，同時保持溫度低於25 °C。將該混合物在19.7-22.4 °C攪拌1.5小時以獲得澄清溶液，將該溶液與AcOH(4.1kg)和水(8.5kg)一起轉移至第二反應容器中。加入5N HCl(由水14.6kg，HCl 37% 12.6kg製備)，同時保持溫度低於25 °C。將該混合物在19.4-20.2 °C攪拌1小時。通過過濾收集獲得的固體，並用1N HCl(4.5kg)洗滌。將收集的固體用1N HCl(42.8kg)處理。將該混合物在19.2-19.3 °C攪拌30分鐘，過濾，並將收集的固體用1N HCl(5.3kg)洗滌。將收集的固體用1N HCl(42.8kg)處理。將該混合物在19.2-19.6 °C攪拌40分鐘，過濾，並將收集的固體用1N HCl(6.1kg)洗滌。固體產物在減壓下於40 °C進行乾燥以獲得4.1kg OAD2-2HCl，其作為白色固體。OAD2-HCl (4.1 kg) was treated with AcOH (8.9 kg), the temperature of the mixture was adjusted to 19.7 °C, and the mixture was stirred at 19.4-19.7 °C for 30 minutes. 5N HCl (prepared from water 5.0kg, 37% HCl 4.2kg) was added over 10 minutes while keeping the temperature below 25°C. The mixture was stirred at 19.1-21.2 °C for 1 hour. Water (84.0 kg) was added over 1 hour while maintaining the temperature below 25°C. The mixture was stirred at 19.7-22.4 °C for 1.5 hours to obtain a clear solution, which was transferred to a second reaction vessel along with AcOH (4.1 kg) and water (8.5 kg). 5N HCl (prepared from water 14.6kg, HCl 37% 12.6kg) was added while keeping the temperature below 25°C. The mixture was stirred at 19.4-20.2 °C for 1 hour. The solid obtained was collected by filtration and washed with 1N HCl (4.5 kg). The collected solid was treated with IN HCl (42.8 kg). The mixture was stirred at 19.2-19.3 °C for 30 minutes, filtered, and the collected solids were washed with 1 N HCl (5.3 kg). The collected solid was treated with IN HCl (42.8 kg). The mixture was stirred at 19.2-19.6 °C for 40 minutes, filtered, and the collected solids were washed with 1N HCl (6.1 kg). The solid product was dried under reduced pressure at 40 °C to obtain 4.1 kg of OAD2-2HCl as a white solid.
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