CN117186053A - Preparation method of lycra ketone intermediate - Google Patents
Preparation method of lycra ketone intermediate Download PDFInfo
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- CN117186053A CN117186053A CN202311154211.6A CN202311154211A CN117186053A CN 117186053 A CN117186053 A CN 117186053A CN 202311154211 A CN202311154211 A CN 202311154211A CN 117186053 A CN117186053 A CN 117186053A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 229920002334 Spandex Polymers 0.000 title claims description 4
- 150000002576 ketones Chemical class 0.000 title claims description 4
- 239000004759 spandex Substances 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229940125904 compound 1 Drugs 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 24
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- 229920000433 Lyocell Polymers 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- 239000002585 base Substances 0.000 claims description 13
- -1 triethylsilyl group Chemical group 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 3
- 125000003003 spiro group Chemical group 0.000 claims description 3
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- 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 claims description 2
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 239000002904 solvent Substances 0.000 abstract description 8
- 125000000217 alkyl group Chemical group 0.000 abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- FOXFZRUHNHCZPX-UHFFFAOYSA-N metribuzin Chemical compound CSC1=NN=C(C(C)(C)C)C(=O)N1N FOXFZRUHNHCZPX-UHFFFAOYSA-N 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000012216 screening Methods 0.000 description 13
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- OMKJDABLEGUPIE-QFKKPMMVSA-N (10s,13r,14r,17r)-4,4,10,13,14-pentamethyl-17-[(2r)-6-methylhept-5-en-2-yl]-1,2,5,6,7,11,12,15,16,17-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C([C@@]12C)CC(=O)C(C)(C)C1CCC1=C2CC[C@]2(C)[C@@H]([C@@H](CCC=C(C)C)C)CC[C@]21C OMKJDABLEGUPIE-QFKKPMMVSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 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 10
- OMKJDABLEGUPIE-UHFFFAOYSA-N euphone Natural products CC12CCC(=O)C(C)(C)C1CCC1=C2CCC2(C)C(C(CCC=C(C)C)C)CCC21C OMKJDABLEGUPIE-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-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](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 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 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 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 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010010369 HIV Protease Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108700022715 Viral Proteases Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- GZVXALXOWVXZLH-AATRIKPKSA-N ethyl (e)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)prop-2-enoate Chemical compound CCOC(=O)\C=C\C1COC(C)(C)O1 GZVXALXOWVXZLH-AATRIKPKSA-N 0.000 description 1
- AUDIVQVJJMELHM-UHFFFAOYSA-N ethyl 3-(2,2-dimethyl-1,3-dioxolan-4-yl)-4-nitrobutanoate Chemical compound CCOC(=O)CC(C[N+]([O-])=O)C1COC(C)(C)O1 AUDIVQVJJMELHM-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical class O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000006514 viral protein processing Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to the field of organic synthesis, in particular to a preparation method of a lexone intermediate, which has the following reaction formula:in PG 1 、PG 2 Independently of each other selected from hydroxy protecting groups or bonded to form a ring, R 3 An alkyl group selected from C1-C6, the preparation method comprising the steps of: and mixing the compound 1, nitromethane and alkali, and then carrying out reaction and post-treatment to obtain the compound 2, wherein the alkali is 1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene. In the method for preparing the lyocell intermediate, the nitromethane is used as a reaction reagent and a solvent simultaneously, and only a catalytic amount of alkali is needed, so that the lyocell intermediate can be prepared with the yield of more than 80 percent, wherein the yieldUp to 97.5%.
Description
Technical Field
The application relates to the field of organic synthesis, in particular to a preparation method of a lankton intermediate.
Background
During processing of viral protein precursors, virally encoded proteases are required, which are essential for viral replication, and interference with protein precursor processing can inhibit the formation of infectious viral particles. Inhibitors of viral proteases are therefore useful in the prevention or treatment of chronic and acute viral infections. (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] furan-3-yl (1S, 2R) -3- [ [ (4-aminophenyl) sulfonyl ] (isobutyl) amino ] -1-benzyl-2-hydroxypropyl carbamate (i.e., lecone) has HIV protease inhibitory activity and is particularly suitable for inhibiting HIV-1 and HIV-2 viruses.
The structure of (3R, 3aS,6 aR) -hexahydrofuro [2,3-b ] furan-3-yl (1S, 2R) -3- [ [ (4-aminophenyl) sulfonyl ] (isobutyl) amino ] -1-benzyl-2-hydroxypropyl carbamate is shown below.
Patent WO 2016207907A1 discloses a process for preparing the above-mentioned compounds I, in which process the compoundsIs an important intermediate for preparing the formula I, and the method for preparing the formula I by using the compound is shown in the following formula.
In the prior art Stereoselective preparation of pyrrolidin-2-ones from Z-enoate derived from D- (+) -mannitol (Tetrahedron Asymmetry,2004, vol.15, #15, p.2313-2314) A process for preparing ethyl 3- (2, 2-dimethyl-1, 3-dioxolan-4-yl) -4-nitrobutyrate is reported herein, using ethyl (E) -3- (2, 2-dimethyl-1, 3-dioxolan-4-yl) acrylate as a reaction substrate, nitromethane as a reaction reagent, DBU as a base, acetonitrile as a solvent, and at-30℃the yield of the product is only 70%.
Disclosure of Invention
The present application has been made to solve the above problems, and an object of the present application is to provide a method for producing a lanosterone intermediate with a high yield.
The application provides a preparation method of a lecone intermediate, which has the following reaction formula:
in PG 1 、PG 2 Independently of one another selected from the group consisting of hydroxy protecting groups or bonded to form a ring,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1, nitromethane and alkali, reacting, post-treating to obtain a compound 2,
the base is 1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene.
Compared with the prior art, the application has the following beneficial effects:
according to the method for preparing the lyocell intermediate, the lyocell intermediate can be prepared in a yield of more than 80% by using nitromethane as a reaction reagent and a solvent and only using a catalytic amount of alkali, wherein the yield can reach 97.5%.
Detailed Description
Embodiments of the specifically disclosed preparation methods of the lexone intermediates are described in detail below.
Definition of terms
The following words, phrases and symbols used in the present specification have the meanings as described below in general unless otherwise indicated.
Generally, the nomenclature used herein (e.g., IUPAC nomenclature) and the laboratory procedures described below (including those used in cell culture, organic chemistry, analytical chemistry, pharmacology, and the like) are those well known and commonly employed in the art. Unless defined otherwise, all scientific and technical terms used herein in connection with the disclosure described herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, in the claims and/or the specification, the terms "a" or "an" when used in conjunction with the term "comprising" or noun may have the meaning of "one" but are also consistent with the meaning of "one or more", "at least one", and "one or more". Similarly, the term "another" or "other" may mean at least a second or more.
It will be understood that whenever aspects are described herein by the terms "comprising" or "including," other similar aspects are provided as described by "consisting of …" and/or "consisting essentially of ….
The term "alkyl" used herein, alone or in combination, may be straight or branched, and the number of carbon atoms may be, for example, C1 to C6, C1 to C5, C1 to C4, C1 to C3, or C1 to C2, etc. By way of example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like.
Herein, bonding to form a ring means forming an aliphatic hydrocarbon ring, an aromatic hydrocarbon ring, an aliphatic heterocyclic ring, an aromatic heterocyclic ring, or a condensed ring thereof. For example PG 1 、PG 2 The bonding after forming a ring may be any of the following structures:
the term "alkoxy" as used herein, alone or in combination, refers to-O (alkyl). Alternatively, the alkyl portion of the alkoxy group may contain 1 to 5 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Alkoxy groups may include, for example, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, and the like.
Preparation method of lycra ketone intermediate
The application provides a preparation method of a lecone intermediate, which has the following reaction formula:
in PG 1 、PG 2 Independently of each other selected from hydroxy protecting groups or bonded to form a ring, R 3 Selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1, nitromethane and alkali, reacting, post-treating to obtain a compound 2,
the base is 1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the molar ratio of the compound 1 to the base is 1: (0.05-1). Alternatively, the molar ratio of the compound 1 to the base may be, for example, 1: (0.05-0.2), 1: (0.2-0.5) or 1: (0.5-1), etc. Preferably, the molar ratio of compound 1 to the base is 1: (0.05-0.2).
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the molar ratio of the compound 1 to the nitromethane is 1: (3-7). Alternatively, the molar ratio of the compound 1 to the nitromethane may be, for example, 1: (3-5), 1: (5-7), 1: (5-6) or 1: (6-7), etc.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the hydroxyl protecting group is selected from any one of trimethylsilyl group, triethylsilyl group, isopropyldimethylsilyl group, isopropyldiethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, triisopropylsilyl group, tert-butyloxycarbonyl group, methoxymethyl group and benzyloxymethyl group.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein PG 1 、PG 2 When bonded to form a ring, the compound 1 is selected from any one of the following compounds:
R 1 ，R 2 independently of one another selected from H, C1-C5 alkyl or bonded to form a spiro ring.
Alternatively, R 1 ，R 2 Independently of each other selected from H.
Alternatively, R 1 ，R 2 Independently of one another, from C1-C5-alkyl. Further alternatively, R 1 ，R 2 Independently of one another, from C1-C4 alkyl, C1-C3 alkyl, C1-C2 alkyl, etc. In particular embodiments, R 1 ，R 2 Independently of each other, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, etc.
Alternatively, R 1 ，R 2 Bonded to form a spiro ring, e.g.
Ar is a substituted or unsubstituted phenyl group, wherein the substituents in the substituted phenyl group are selected from C1-C5 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy and the like. The number of substituents in the substituted phenyl group may be 1 or more.
Preferably, compound 1 is any one of the following compounds:
R 3 selected from C1-C6 alkyl groups. Alternatively, R 3 Selected from C1-C5, C1-C4, C1-C3 or C1-C2, etc. In particular embodiments, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, 1-methyl-butyl, 1-ethyl-butyl, pentyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and the like.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the compound 1 isWherein PG 1 、PG 2 、R 3 As defined above. Preferably, the structure of compound 1 may be, for example +.>More preferably, the structure of compound 1 may be, for example +.>
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the compound 1 isWherein PG 1 、PG 2 、R 3 As defined above.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the compound 2 isWherein PG 1 、PG 2 、R 3 As defined above.
Preferably, the structure of compound 2 may be, for exampleMore preferably, the structure of compound 2 may be, for example +.>
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the reaction temperature is 10-50 ℃. In a specific embodiment, the reaction temperature may be, for example, 10 to 20 ℃,20 to 30 ℃, 30 to 40 ℃, 40 to 50 ℃, or the like.
The preparation method of the lanosterone intermediate provided by the application can also have the following characteristics: wherein the post-treatment comprises adding water, adjusting pH to < 7 with acid, extracting with ethyl acetate, washing the organic phase with NaCl aqueous solution, and rotary-evaporating the organic phase until no fraction is present.
The present application will be described in detail with reference to the following examples, so that the technical means, the creation characteristics, the achievement of the purpose and the effect achieved by the present application are easily understood.
In the examples described below, each of the reaction materials was a commercially available product unless otherwise specified.
In the following examples, DBU is 1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene, cas No.: 6674-22-2.
In the examples below, dr is the ratio of diastereomers.
In the embodiments described in the following description of the embodiments,the yield was calculated by: yield = (mass of actual product/mass of theoretical product) 100％。
Example 1 ]
Preparation of Compound 2a
This example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following steps:
5g of Compound 1a (25 mmol,1.0 eq), 7.6g of nitromethane (125 mmol,5 eq) and 0.19g of DBU (1.25 mmol,0.05 eq) are added to a three-necked flask, reacted for 2h at 20℃with water, pH < 7 adjusted by adding 18% by mass of citric acid, extracted with ethyl acetate, the organic phase is washed with 10% by mass of aqueous NaCl solution, the organic phase is distilled off in a rotary manner until no fraction is obtained, 6.37g of Compound 2a is obtained, the structure is confirmed by hydrogen spectrum and quantitative carbon spectrum in a yield of 97.5%, and the dr value is calculated to be 9.4:1. Wherein the yield was calculated on the basis of compound 1a, in this example the theoretical product was 25mmol. Compound 2a yield= [ 6.37/(0.025 x 261.27) ]x100% = 97.5%. Other embodiments the calculation is described with reference to embodiment 1.
Example 2 ]
Screening of DBU usage
In this example, the amounts of DBU used were selected based on example 1, and the procedure was the same as that described in example 1, except for the parameters listed in the following table.
The screening results are shown in Table 1.
TABLE 1 screening of DBU usage
| Sequence number | DBU dosage | Product yield (%) | dr value |
| 1 | 0.76g(0.2eq) | 95.6 | 9.4:1 |
| 2 | 0.38g(0.1eq) | 97.4 | 9.4:1 |
| 3 | 3.8g(1.0eq) | 93.6 | 9.4:1 |
As is clear from the above table, when the amount of DBU used was 1.0eq, DBU was in the range of 0.05eq to 1.0eq, and the yield of the product was 90% or more. When DBU is in the range of 0.05 eq-0.2 eq, the yield of the product is over 95 percent. In this example, the product yield decreased slightly with increasing amount of base, probably because a large amount of base makes the reaction system using nitromethane as a solvent viscous and difficult to stir.
Example 3 ]
Screening of nitromethane usage
In this example, the amounts of nitromethane used were selected based on example 1, and the procedure was the same as described in example 1, except for the parameters listed in the following table.
The screening results are shown in Table 2.
TABLE 2 screening of nitromethane dosage
| Sequence number | Nitromethane dosage | Product yield (%) |
| 1 | 3.04g(2.0eq) | N.R |
| 2 | 1.52g(1.0eq) | N.R |
| 3 | 4.56g(3.0eq) | 80.7％ |
As is clear from the above table, when the amount of nitromethane used is small, 1eq or 2eq, the reaction system becomes too viscous, and a large amount of raw materials remain, resulting in poor reaction effect. Thus, reducing the amount of nitromethane will result in a significant reduction in the rate of reaction.
Example 4 ]
Screening of reaction temperature
In this example, the reaction temperature was selected, and the reaction formula was as follows:
the method comprises the following steps:
5g of compound 1a (25 mmol,1.0 eq), 7.6g of nitromethane (125 mmol,5 eq) and 0.76g of DBU (5 mmol,0.2 eq) are introduced into a three-necked flask and reacted for 2h at a temperature, water is added, the pH of the solution is adjusted to < 7 by adding 18% by mass of citric acid, extraction is carried out with ethyl acetate, the organic phase is washed with 10% by mass of aqueous NaCl and the organic phase is distilled off until no fraction is obtained.
The screening results are shown in Table 3.
TABLE 3 screening of reaction temperatures
| Sequence number | Reaction temperature (. Degree. C.) | Product yield (%) |
| 1 | 50 | 97.4 |
| 2 | 30 | 96.5 |
| 3 | 10 | 94.4 |
As is clear from the above table, the yield of the product is above 90% when the reaction temperature is between 10 ℃ and 50 ℃ by screening the reaction temperature of the application. In this example, the product yield remained essentially stationary with increasing reaction temperature, but slightly fluctuating, possibly due to experimental operating errors and some unavoidable systematic errors.
Comparative example 1 ]
Preparation method of compound 2a
This example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following steps:
24g of Compound 1a (0.12 mol,1.0 eq), 8g of nitromethane (0.13 mol,1.1 eq), 18.2g of DBU (0.12 mol,1 eq) and 7.44g (0.23 mol,2.0 eq) of methanol were added to a three-necked flask, reacted at 20-25℃for 2h, distilled to remove methanol without fractions, water was added, pH of the solution was adjusted to < 7 by adding 18% by mass of citric acid, extracted with ethyl acetate, the organic phase was washed with 10% by mass of aqueous NaCl solution, and distilled to without fractions, yielding 22.1g of Compound 2a in a yield of 70.7%.
Comparative example 2 ]
Preparation method of compound 2a
This example provides a method for preparing compound 2a, which has the following reaction formula:
the method comprises the following steps:
24g of Compound 1a (0.12 mol,1.0 eq), 8g of nitromethane (0.13 mol,1.1 eq), 0.91g of DBU (0.006mol, 0.05 eq) and 7.44g (0.23 mol,2.0 eq) of methanol were added to a three-necked flask, reacted at 20-25℃for 2h, distilled to remove methanol without fractions, water was added, pH of the solution was adjusted to < 7 by adding 18% by mass of citric acid, extracted with ethyl acetate, the organic phase was washed with 10% by mass of aqueous NaCl solution, and distilled to remove fractions by spinning to obtain 19.48g of Compound 2a in 62.2% yield.
As can be seen from comparative examples 1 and 2, when the solvent is methanol, the yield of the product is significantly reduced.
Effects and effects of the examples
According to the method for preparing the lyocell intermediate according to the above examples, the lyocell intermediate can be prepared in a yield of 80% or more with nitromethane as a reaction reagent and a solvent and only a catalytic amount of a base, wherein the yield can be up to 97.5%.
Further, by screening the DBU dosage of the application, when the compound 1a is 1.0eq, the DBU dosage is in the range of 0.05eq to 1.0eq, and the yield of the product is above 90%. When DBU is in the range of 0.05 eq-0.2 eq, the yield of the product is over 95 percent. In the present application, therefore, the molar ratio of compound 1 to the base is 1: (0.05-1), preferably 1: (0.05-0.2).
Further, by screening the amount of nitromethane of the present application, when the amount of nitromethane is small, 1eq or 2eq, the reaction system becomes too viscous, resulting in a large amount of raw materials remaining, and the reaction effect is poor. Thus, reducing the amount of nitromethane will result in a significant reduction in the rate of reaction. The molar ratio of the compound 1 to the nitromethane in the application is 1: (3-7), preferably 1: (5-7).
Further, through screening the reaction temperature, the yield of the product is over 90 percent when the reaction temperature is between 10 ℃ and 50 ℃. When the reaction temperature is between 20 ℃ and 50 ℃, the yield of the product is over 95 percent.
Further, when the solvent is methanol, the yield of the product is significantly reduced. And when methanol is not contained and nitromethane is used as a reaction reagent and a solvent, the yield of the product is obviously improved.
The above embodiments are preferred examples of the present application, and are not intended to limit the scope of the present application.
The applicant states that the present application illustrates the preparation of the present application of the lexone intermediate by the above examples, but the present application is not limited to the above examples, i.e. it does not mean that the present application must be carried out in dependence on the above examples. It should be apparent to those skilled in the art that any modification of the present application, equivalent substitution of raw materials for the product of the present application, addition of auxiliary components, selection of specific modes, etc., falls within the scope of the present application and the scope of disclosure.
The above embodiments are preferred examples of the present application, and are not intended to limit the scope of the present application. However, the present application is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present application within the scope of the technical concept of the present application, and all the simple modifications belong to the protection scope of the present application.
In addition, the specific features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various possible combinations are not described further.
Claims (10)
1. A preparation method of a lycra ketone intermediate, which is characterized by comprising the following reaction formula:
in PG 1 、PG 2 Independently of one another selected from the group consisting of hydroxy protecting groups or bonded to form a ring,
R 3 selected from the group consisting of C1-C6 alkyl,
the preparation method comprises the following steps:
mixing the compound 1, nitromethane and alkali, reacting, post-treating to obtain a compound 2,
the base is 1, 8-diazabicyclo-bicyclo (5, 4, 0) -7-undecene.
2. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the molar ratio of the compound 1 to the base is 1: (0.05-1).
3. A process for the preparation of a lecone intermediate according to claim 2, characterized in that:
wherein the molar ratio of the compound 1 to the base is 1: (0.05-0.2).
4. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the molar ratio of the compound 1 to the nitromethane is 1: (3-7);
and/or the reaction temperature is 10-50 ℃.
5. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the hydroxyl protecting group is selected from any one of trimethylsilyl group, triethylsilyl group, isopropyl dimethylsilyl group, isopropyl diethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, triisopropylsilyl group, tert-butyloxycarbonyl group, methoxymethyl group and benzyloxymethyl group.
6. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the compound 1 is selected from any one of the following compounds:
R 1 ，R 2 independently of one another selected from H, C1-C5 alkyl or bonded to form a spiro ring,
ar is a substituted or unsubstituted phenyl group,
R 3 as defined in claim 1.
7. A process for the preparation of a lyocell intermediate according to claim 1 or 6, characterized in that:
the compound 1 is selected from any one of the following compounds:
wherein R is 3 As defined in claim 1.
8. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the compound 1 isWherein PG 1 、PG 2 、R 3 As defined in claim 1.
9. The process for the preparation of a lecone intermediate according to claim 8, wherein:
the compound 1 isWherein PG 1 、PG 2 、R 3 As defined in claim 1.
10. A process for the preparation of a lecone intermediate according to claim 1, characterized in that:
the compound 2 isWherein PG 1 、PG 2 、R 3 As defined in claim 1.
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