CN114702425B - Process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates - Google Patents
Process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates Download PDFInfo
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- CN114702425B CN114702425B CN202210311825.XA CN202210311825A CN114702425B CN 114702425 B CN114702425 B CN 114702425B CN 202210311825 A CN202210311825 A CN 202210311825A CN 114702425 B CN114702425 B CN 114702425B
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- 150000001294 alanine derivatives Chemical class 0.000 title claims abstract description 31
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000000034 method Methods 0.000 title claims description 14
- 230000008569 process Effects 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims abstract description 17
- 230000009471 action Effects 0.000 claims abstract description 10
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 230000000911 decarboxylating effect Effects 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 239000003960 organic solvent Substances 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 18
- 229910021529 ammonia Inorganic materials 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- 150000002430 hydrocarbons Chemical group 0.000 claims description 12
- 102000003929 Transaminases Human genes 0.000 claims description 11
- 108090000340 Transaminases Proteins 0.000 claims description 11
- FRKGSNOMLIYPSH-VKHMYHEASA-N (3s)-3-hydroxypyrrolidin-2-one Chemical compound O[C@H]1CCNC1=O FRKGSNOMLIYPSH-VKHMYHEASA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 8
- -1 sodium alkoxide Chemical class 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- 108090000698 Formate Dehydrogenases Proteins 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000005515 coenzyme Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- 230000020477 pH reduction Effects 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 239000012141 concentrate Substances 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000012752 auxiliary agent Substances 0.000 claims description 3
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 150000008575 L-amino acids Chemical class 0.000 claims description 2
- 239000005456 alcohol based solvent Substances 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000001276 controlling effect Effects 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 230000001105 regulatory effect Effects 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 230000006103 sulfonylation Effects 0.000 description 3
- 238000005694 sulfonylation reaction Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- YSEKNCXYRGKTBJ-UHFFFAOYSA-N dimethyl 2-hydroxybutanedioate Chemical compound COC(=O)CC(O)C(=O)OC YSEKNCXYRGKTBJ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- 108091005532 SARS-CoV-2 main proteases Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZOKLUHBZBGHBAB-UHFFFAOYSA-N dimethyl 2-oxobutanedioate Chemical compound COC(=O)CC(=O)C(=O)OC ZOKLUHBZBGHBAB-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-OUBTZVSYSA-N sodium-24 Chemical compound [24Na] KEAYESYHFKHZAL-OUBTZVSYSA-N 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivative and an intermediate, which comprises the steps of reacting a compound C with a compound B under the action of strong alkali to generate a compound G, hydrolyzing and decarboxylating the compound G to obtain the intermediate, and converting the intermediate into the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative. The invention uses the intermediate to prepare the (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivative, has simple preparation method and mild reaction condition, remarkably improves the yield of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative, and is particularly suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative and an intermediate.
Background
PF-07321332 is a new anti-new coronavirus drug recently introduced by the company of the best, and has higher anti-new coronavirus activity proved by preliminary clinical practice. The chemical structure of PF-07321332 is shown in the following formula:
as can be seen from the above formula, PF-07321332 is composed of three chiral intermediates (see formulas (A), (B), (C) below) in its chemical structure.
Wherein, (A) has been commercially produced, (B) has also been reported in the synthesis literature, and (C) can be obtained from (f) treatment with Burgess Reagent (reference US 11124497), the relevant reaction formula is as follows:
the synthesis of compound (f) has also been reported in the literature, for example Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease,Science(Washington,DC,United States),368(6497),1331-1335;2020a discloses the following synthetic route for (f).
However, the above route has the following disadvantages: firstly, the hydrocarbylation reaction of bromoacetonitrile and L-glutamate requires a reaction condition of ultralow temperature of-78 ℃ and harsh reaction condition; secondly, the strong alkali LiHMDS is expensive, which clearly increases the preparation cost; thirdly, the two-step reaction yield of hydrocarbylation and reduction cyclization is not high (about 22% of the two-step yield), and the two-step reaction products of hydrocarbylation and reduction cyclization are required to be separated and purified by a column, so that the method is complex in operation and not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives and intermediates, which have mild reaction conditions, simple operation, high purity and high yield and are suitable for industrial production.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a process for the preparation of an intermediate having the formula The preparation method comprises the steps of reacting a compound C and a compound B under the action of strong alkali to generate a compound G, and then hydrolyzing and decarboxylating the compound G to obtain the intermediate, wherein the structural formula of the compound C isThe structural formula of the compound B is/>The structural formula of the compound G isR 1、R2 in the structural formula is independently selected from hydrocarbon groups with 1-6 carbon atoms, and Q 2 is selected from any one of substituted or unsubstituted aryl and hydrocarbon groups with 1-3 carbon atoms in the structural formula R 3SO2,R3.
Preferably, the strong base is selected from one or more of NaH, sodium alkoxide, potassium alkoxide, DBU, and LiHMDS.
Further preferably, the sodium alkoxide includes, but is not limited to, one or more of sodium methoxide, sodium ethoxide, and the potassium alkoxide includes, but is not limited to, potassium tert-butoxide.
Preferably, the molar ratio of the strong base to the compound C is (0.8-1.2): 1.
Further preferably, the molar ratio of the strong base to the compound C is (0.8 to 1.0): 1.
Preferably, the reaction temperature of the compound C and the compound B is controlled to be 0 to 100 ℃.
Further preferably, the reaction temperature of the compound C and the compound B is controlled to be 10 to 70 ℃.
Still more preferably, the reaction temperature of the compound C and the compound B is controlled to be 40 to 70 ℃.
According to some preferred embodiments, the compound G is obtained by reacting the compound C with the strong base at 15 to 35 ℃ for 0.1 to 1 hour, and then with the compound B at 40 to 70 ℃ for 1 to 5 hours.
Preferably, the compound C and the compound B are reacted in the presence of an organic solvent selected from one or more of DMF, DMSO, THF, toluene and an alcohol solvent.
Further preferably, the compound C and the strong base are reacted in the presence of a first organic solvent, then the first organic solvent is distilled off, and then reacted with the compound B in the presence of a second organic solvent, the first organic solvent and the second organic solvent being independently selected from one or more of DMF, DMSO, THF, toluene and an alcohol solvent, respectively, the first organic solvent and the second organic solvent being different.
Preferably, the hydrolytic decarboxylation comprises reacting the compound G in the presence of sodium hydroxide and an organic solvent, followed by acidification with hydrochloric acid to give the intermediate.
Further preferably, the sodium hydroxide is fed in the form of an aqueous sodium hydroxide solution having a mass concentration of 5 to 15%.
Still further preferably, the feeding mass ratio of the sodium hydroxide aqueous solution to the hydrochloric acid is (1.5-3): 1.
Still more preferably, the feeding mass ratio of the sodium hydroxide aqueous solution to the hydrochloric acid is (2.5-3): 1.
Preferably, the organic solvent is selected from one or more of DMF, DMSO, THF, toluene and alcohol solvents.
Preferably, the reaction temperature of the hydrolytic decarboxylation is controlled to be 0-100 ℃.
Further preferably, the reaction temperature of the hydrolytic decarboxylation is controlled to be 0 to 50 ℃.
Still more preferably, the reaction temperature of the hydrolytic decarboxylation is controlled to be 10 to 30 ℃.
Preferably, the preparation method further comprises the steps of adding an extractant into the system after acidification for extraction, concentrating an organic phase obtained by extraction and recrystallizing a concentrate obtained by concentration, wherein the extractant is one or more of dichloromethane, ethyl acetate or toluene, and the mixed solvent is ethyl acetate and n-heptane, and the volume ratio of the ethyl acetate to the n-heptane is 1: (3-5).
Preferably, the preparation method further comprises the step of reacting (S) -3-hydroxy-2-pyrrolidone with a sulfonylation reagent under the action of triethylamine to generate the compound B, wherein the sulfonylation reagent has a structural formula of R 3SO2 X; wherein, R 3 is the same as R 3 in Q 2, and X is any one of fluorine, chlorine, bromine and iodine.
Further preferably, the molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the sulfonylation agent is 1 (1-1.4).
Still more preferably, the molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the sulfonylating agent is 1 (1.1-1.3).
Preferably, the feeding molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.2-1.8).
Further preferably, the molar ratio of the (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.4-1.6).
Preferably, the temperature of the reaction is controlled to be 20 to 50 ℃.
Further preferably, the temperature of the reaction is controlled to 25 to 40 ℃.
In a second aspect the present invention provides a process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives by preparing an intermediate and then converting said intermediate into (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives; wherein the intermediate is prepared according to the preparation method, and the structural formula of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative is
Preferably, converting the intermediate to the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative comprises: reacting said intermediate with an ammonia donor under the action of a transaminase to form a compound e, and then converting said compound e into said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative; wherein the structural formula of the compound e is
Preferably, the intermediate is reacted with the ammonia donor in the presence of formate dehydrogenase, coenzyme and co-agent.
Further preferably, the ammonia donor is selected from ammonium formate and/or L-amino acids.
Still more preferably, the ratio of the intermediate to the ammonia donor is 1 (0.8 to 1) by mass.
Preferably, the feed mass ratio of the transaminase to the formate dehydrogenase to the coenzyme is 1: (0.1-0.3): (0.05-0.2).
Further preferably, the feed mass ratio of the transaminase to the formate dehydrogenase to the coenzyme is 1: (0.15-0.25): (0.1-0.15).
Preferably, the feeding mass ratio of the intermediate to the transaminase is 1: (0.01-0.1).
Further preferably, the feeding mass ratio of the intermediate to the transaminase is 1: (0.03-0.08).
Preferably, the auxiliary agent is an aqueous sodium hydroxide solution.
Further preferably, the auxiliary is used to adjust the pH of the reaction system to 7.5 to 8.5.
Preferably, the temperature at which the intermediate reacts with the ammonia donor is controlled to be 20-40 ℃.
Preferably, the conversion of said compound e into said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative comprises: compound e is reacted with thionyl chloride and then with ammonia to form the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative.
Further preferably, the molar ratio of the compound e to the thionyl chloride is 1 (0.8-1.2).
Further preferably, the mass concentration of ammonia in the system is controlled to be 10 to 20%.
In a third aspect, the present invention provides an intermediate of the formula
In a fourth aspect, the invention provides the use of an intermediate in the medical field.
Preferably, the intermediates are used in the preparation of anti-neocoronavirus drugs.
Further preferably, the intermediate is used for preparing PF-07321332.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
The preparation method of the intermediate has mild reaction conditions and simple operation, the purity of the prepared intermediate can reach 98 percent or more, the yield can reach 76 percent or more, and the prepared intermediate can be used for synthesizing (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives;
The invention uses the intermediate to prepare the (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivative, has simple preparation method and mild reaction condition, remarkably improves the yield of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative, and is particularly suitable for industrial production.
Detailed Description
The synthesis of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives in the prior art mainly has the problems of harsh reaction conditions, complicated operation and low yield, and based on the defects of the prior art, the inventor provides the scheme through a great deal of experimental study, and the scheme is further described below.
A process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives comprising the steps of:
(1) Reacting (S) -3-hydroxy-2-pyrrolidone (compound a) with a sulfonylating agent under the action of triethylamine to produce compound B;
(2) Reacting the compound B with the compound C under the action of strong alkali to generate a compound G, and then hydrolyzing and decarboxylating the compound G to obtain an intermediate (compound d);
(3) Reacting the intermediate with an ammonia donor under the action of a transaminase to form a compound e;
(4) Converting compound e into the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative (compound f).
The preparation route of the above steps is shown below.
According to the invention, the starting material (C) reacts with strong alkali to generate carbanion, then the carbanion reacts with 3-substituted (S) -pyrrolidone (B) to generate SN 2 nucleophilic substitution reaction, then the reaction product is hydrolyzed and decarboxylated to prepare (d), then the reaction product is catalyzed by transaminase and reacts with ammonia donor to generate (e), and finally the reaction product is reacted to obtain the corresponding target product (f), and the steps are not required to be separated and purified by columns, so that the method is simple in steps, mild in reaction conditions, high in product yield and easy for industrial production.
According to the present invention, step (1) is carried out in the presence of a solvent, including but not limited to methylene chloride.
According to the invention, R 1、R2 is independently selected from hydrocarbon groups with 1-6 carbon atoms, and Q 2 has a structural formula of R 3SO2,R3 and is selected from any one of substituted or unsubstituted aryl and hydrocarbon groups with 1-3 carbon atoms. The hydrocarbon group in the present invention includes saturated hydrocarbon groups and unsaturated hydrocarbon groups, and the saturated hydrocarbon groups include alkyl groups, cycloalkyl groups such as methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, n-pentyl groups, isopentyl groups, hexyl groups, cyclopropyl groups, cyclobutyl groups, cyclopentyl groups, cyclohexyl groups, and the like. Unsaturated hydrocarbon groups include alkenyl groups, hydrocarbon groups, cycloalkenyl groups, phenyl groups, such as, for example, alkenyl groups, vinyl groups, ethynyl groups, propenyl groups, allyl groups, propargyl groups, hexenyl groups, cyclopropenyl groups, phenyl groups, and the like. Substituted aryl groups include, but are not limited to, tolyl.
According to the invention, the step (1) further comprises the steps of adding water to delaminate the system after the reaction is finished, then washing the organic layer with water, and then drying the organic layer, wherein the dried organic layer can be directly used for the next reaction or dissolved in an organic solvent and then used for the next reaction.
Further, methods of drying the organic layer include, but are not limited to, using a desiccant and/or concentrated drying. The drying agent may be, for example, anhydrous sodium sulfate.
According to some specific and preferred embodiments, the preparation route for the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative may be:
Wherein starting material (a) can be synthesized from inexpensive L-glutamic acid by the following route, preparation method reference (EP 430234; CN1066842; synlett, (13), 2028-2032; 2008).
The raw material (c) can be obtained by the condensation reaction of oxalic ester and acetic ester through claisen ester, and the reaction route is as follows:
Or is obtained by oxidation of dimethyl malate, and the reaction route is as follows:
the invention is further described below with reference to examples. The present invention is not limited to the following examples. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use, and the implementation conditions which are not noted are conventional conditions in the industry. The technical features of the various embodiments of the present invention may be combined with each other as long as they do not collide with each other.
Unless otherwise specified, room temperature in the examples below refers to 20 to 25 ℃.
Example 1
Preparation of Compound (b)
Into a reaction flask, 100ml of methylene chloride, 10.1 g (100 mmol) of (S) -3-hydroxy-2-pyrrolidone (a) and 22.8 g (120 mmol) of p-toluenesulfonyl chloride were added, and the mixture was stirred and dissolved, 15 g (148 mmol) of triethylamine was added dropwise at room temperature, and after completion of the dropwise reaction, the reaction was kept at 30℃to 35℃for 5 hours, 50 g of water was added, the mixture was separated, the organic layer was washed with water, dried over anhydrous sodium sulfate, the drying agent was removed by filtration, and the organic phase was concentrated to dryness and diluted with 50ml of DMF and was directly used for the next reaction.
Example 2
Preparation of Compound (d)
In another reaction flask, 50ml of toluene, 7.6 g (140 mmol) of sodium methoxide and 24 g (150 mmol) of dimethyl 2-oxosuccinate (c) were placed, the reaction was stirred at room temperature for half an hour, toluene was distilled off under reduced pressure, 50ml of DMF was added to the residue, the DMF solution containing (b) prepared in example 1 was slowly added dropwise after stirring, the reaction was carried out at 60-65℃for 3 hours, after the reaction, DMF was recovered by distillation under reduced pressure, and the residue was cooled to room temperature.
120 G of 10% aqueous NaOH solution, 50ml of toluene were added to the residue, the reaction was carried out at room temperature for 2 hours, the organic layer was discarded, 45 g of concentrated hydrochloric acid was added dropwise to the aqueous layer to acidify it, 100ml of methylene chloride was added to extract, the organic layer was concentrated, and the concentrate was added in a volume ratio of 2: ethyl acetate of 8: 80ml of n-heptane is recrystallized, 13 g of product (d) is obtained, the molar yield is 76%, the HPLC purity is 98%, and the ee% is 97%.
Example 3
Preparation of Compound (e)
Weighing 10g of a substrate (d), adding 15ml of water, and adjusting the pH to 8 by using 40% NaOH aqueous solution to prepare a substrate liquid; in a 250ml three-port flask, 9g of ammonium formate and 45ml of water were weighed, pH=8.0 was adjusted with 40% NaOH aqueous solution, the temperature was raised to 30℃and 0.5g of transaminase (L-TA of Suzhou Han Enzymosan Biotechnology Co., ltd.), 0.1g of formate dehydrogenase and 0.06g of coenzyme NAD were added, and the substrate liquid was added dropwise to the reaction flask with a constant flow pump and completed at about 5 hours, and the reaction was carried out for 24 hours, with a conversion rate of 99% by HPLC and an ee% of 99.5%.
Example 4
Preparation of Compound (f)
100Ml of methanol and 17.2 g (100 mmol) (e) of the mixture are added into a reaction bottle, the mixture is cooled to 10 ℃, 12 g (100 mmol) of SOCl 2 is added dropwise, the mixture is reacted for 20 hours at room temperature after the dropwise addition, acid and methanol are removed under reduced pressure after the reaction is finished, 100ml of methanol is added, the mixture is cooled to 0 ℃, ammonia is introduced to ensure that the ammonia mass concentration in the reaction liquid reaches 15%, the ammonia introduction is stopped, the reaction is carried out for 24 hours at room temperature, part (about 2/3) of methanol is gradually heated to normal pressure, a solid product is separated out, the mixture is cooled to-5 ℃ and filtered, a filter cake is washed by a small amount of cold methanol, and the product (f) of 17.2 g is obtained, the yield is 83%, HPLC98% and ee% is 99% after the drying.
The present invention has been described in detail with the purpose of enabling those skilled in the art to understand the contents of the present invention and to implement the same, but not to limit the scope of the present invention, and all equivalent changes or modifications made according to the spirit of the present invention should be included in the scope of the present invention.
Claims (9)
1. A preparation method of an intermediate is characterized in that,
The structural formula of the intermediate is
The preparation method comprises the steps of reacting a compound C with a compound B under the action of strong alkali to generate a compound G, then hydrolyzing and decarboxylating the compound G to obtain the intermediate,
Wherein,
The structural formula of the compound C is
The structural formula of the compound B is
The structural formula of the compound G is
R 1、R2 in the structural formula is independently selected from hydrocarbon groups with 1-6 carbon atoms, and Q 2 has the structural formula of R 3SO2,R3 which is selected from any one of substituted or unsubstituted aryl and hydrocarbon groups with 1-3 carbon atoms;
Firstly, reacting the compound C with the strong base at 15-35 ℃ for 0.1-1 h in the presence of a first organic solvent, then steaming out the first organic solvent, and then reacting with the compound B at 40-70 ℃ for 1-5 h in the presence of a second organic solvent to obtain the compound G, wherein the first organic solvent and the second organic solvent are different;
The hydrolysis decarboxylation comprises the steps of firstly enabling the compound G to react in the presence of sodium hydroxide and an organic solvent, then adding hydrochloric acid for acidification, adding an extractant into a system for extraction after acidification, concentrating an organic phase obtained by extraction, and recrystallizing a concentrate obtained by concentration to obtain the intermediate, wherein the extractant is one or more of dichloromethane, ethyl acetate or toluene, and recrystallizing by using a mixed solvent, and the mixed solvent is ethyl acetate and n-heptane.
2. The method for preparing an intermediate according to claim 1, wherein the strong base is one or more selected from NaH, sodium alkoxide, potassium alkoxide, DBU and LiHMDS, and the molar ratio of the strong base to the compound C is (0.8-1.2): 1, a step of;
and/or reacting the compound C and the compound B in the presence of an organic solvent selected from one or more of DMF, DMSO, THF, toluene, and an alcohol solvent.
3. The method for preparing an intermediate according to claim 1, wherein the sodium hydroxide is fed in the form of 5-15% aqueous sodium hydroxide solution, the organic solvent is one or more selected from DMF, DMSO, THF, toluene and alcohol solvents, and the reaction temperature is controlled to be 0-100 ℃.
4. The method for preparing an intermediate according to claim 1, further comprising the steps of adding an extractant to the system after the acidification for extraction, concentrating an organic phase obtained by the extraction and recrystallizing a concentrate obtained by the concentration, wherein the extractant is one or more selected from dichloromethane, ethyl acetate or toluene, and the mixed solvent is ethyl acetate and n-heptane, and the volume ratio of the ethyl acetate to the n-heptane is 1: (3-5).
5. The process for preparing an intermediate according to claim 1, further comprising reacting (S) -3-hydroxy-2-pyrrolidone with a sulfonylating agent having the structural formula R 3SO2 X under the action of triethylamine to produce the compound B;
Wherein, R 3 is the same as R 3 in Q 2, X is any one of fluorine, chlorine, bromine and iodine, the feeding molar ratio of (S) -3-hydroxy-2-pyrrolidone to the sulfonylating agent is 1 (1-1.4), and the feeding molar ratio of (S) -3-hydroxy-2-pyrrolidone to the triethylamine is 1: (1.2-1.8), and controlling the temperature of the reaction to be 20-50 ℃.
6. A process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives, characterized in that an intermediate is prepared and then said intermediate is converted into (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives; wherein the intermediate is prepared according to the preparation method as claimed in any one of claims 1 to 5,
The structural formula of the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative is
7. The method for producing (S) -2-amino- (S) -3- [ pyrrolidone-2 '] alanine derivatives according to claim 6, wherein converting the intermediate into (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives comprises: reacting said intermediate with an ammonia donor under the action of a transaminase to form a compound e, and then converting said compound e into said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative;
wherein,
The structural formula of the compound e is
8. The process for the preparation of (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivatives according to claim 7, wherein said intermediate is reacted with said ammonia donor in the presence of formate dehydrogenase, coenzyme, and adjunct; wherein the ammonia donor is selected from ammonium formate and/or L-amino acid, and the feeding mass ratio of the intermediate to the ammonia donor is 1:
(0.8-1); the feeding mass ratio of the transaminase to the formate dehydrogenase to the coenzyme is 1: (0.1-0.3):
(0.05-0.2), wherein the feeding mass ratio of the intermediate to the aminotransferase is 1: (0.01-0.1); the auxiliary agent is sodium hydroxide aqueous solution, the pH of the reaction system is regulated to 7.5-8.5 by using the auxiliary agent, and the temperature of the reaction is controlled to be 20-40 ℃;
And/or, the conversion of said compound e to said (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative comprises: reacting compound e with thionyl chloride and then with ammonia to produce the (S) -2-amino- (S) -3- [ pyrrolidone-2' ] alanine derivative; wherein the feeding mole ratio of the compound e to the thionyl chloride is 1 (0.8-1.2), and the mass concentration of ammonia in the system is controlled to be 10-20%.
9. An intermediate prepared by the process according to any one of claims 1 to 5, wherein the intermediate has the structural formula
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4342776A (en) * | 1979-11-05 | 1982-08-03 | Merck & Co., Inc. | 4-Substituted-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase |
| JP2009242244A (en) * | 2008-03-28 | 2009-10-22 | Nippon Nohyaku Co Ltd | Method for producing pyrazine derivative and intermediate of the same |
| CN101768102A (en) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
| CN103014081A (en) * | 2012-12-19 | 2013-04-03 | 苏州汉酶生物技术有限公司 | Biological preparation method of 3-amino-4-(2,4,5-trifluorophenyl)methyl butyrate |
| CN104045637A (en) * | 2014-04-18 | 2014-09-17 | 河北科技大学 | Apixaban preparation method |
| CN106191148A (en) * | 2016-07-27 | 2016-12-07 | 苏州汉酶生物技术有限公司 | (R) biological preparation method of 3 amino 4 (2,4,5 trifluorophenyl) tert-butyl acetate |
| CN108947884A (en) * | 2018-06-29 | 2018-12-07 | 江苏美迪克化学品有限公司 | A kind of Preparation Method And Their Intermediate of imrecoxib |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11351149B2 (en) * | 2020-09-03 | 2022-06-07 | Pfizer Inc. | Nitrile-containing antiviral compounds |
-
2022
- 2022-03-28 CN CN202210311825.XA patent/CN114702425B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4342776A (en) * | 1979-11-05 | 1982-08-03 | Merck & Co., Inc. | 4-Substituted-3-hydroxy-3-pyrroline-2,5-dione inhibitors of glycolic acid oxidase |
| JP2009242244A (en) * | 2008-03-28 | 2009-10-22 | Nippon Nohyaku Co Ltd | Method for producing pyrazine derivative and intermediate of the same |
| CN101768102A (en) * | 2009-01-05 | 2010-07-07 | 浙江华海药业股份有限公司 | New preparation method of atorvastatin calcium 1H-pyrrole derivatives |
| CN103014081A (en) * | 2012-12-19 | 2013-04-03 | 苏州汉酶生物技术有限公司 | Biological preparation method of 3-amino-4-(2,4,5-trifluorophenyl)methyl butyrate |
| CN104045637A (en) * | 2014-04-18 | 2014-09-17 | 河北科技大学 | Apixaban preparation method |
| CN106191148A (en) * | 2016-07-27 | 2016-12-07 | 苏州汉酶生物技术有限公司 | (R) biological preparation method of 3 amino 4 (2,4,5 trifluorophenyl) tert-butyl acetate |
| CN108947884A (en) * | 2018-06-29 | 2018-12-07 | 江苏美迪克化学品有限公司 | A kind of Preparation Method And Their Intermediate of imrecoxib |
Non-Patent Citations (1)
| Title |
|---|
| Asymmetric approach towards the total synthesis of (t)-actinopyllic acid;Fei Xue et al.;《Tetrahedron》;第73卷;2109-2115 * |
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