CN114349693B - Preparation method of dolutegravir key intermediate - Google Patents
Preparation method of dolutegravir key intermediate Download PDFInfo
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- CN114349693B CN114349693B CN202111660336.7A CN202111660336A CN114349693B CN 114349693 B CN114349693 B CN 114349693B CN 202111660336 A CN202111660336 A CN 202111660336A CN 114349693 B CN114349693 B CN 114349693B
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- 229960002542 dolutegravir Drugs 0.000 title claims abstract description 15
- RHWKPHLQXYSBKR-BMIGLBTASA-N dolutegravir Chemical compound C([C@@H]1OCC[C@H](N1C(=O)C1=C(O)C2=O)C)N1C=C2C(=O)NCC1=CC=C(F)C=C1F RHWKPHLQXYSBKR-BMIGLBTASA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- 238000006460 hydrolysis reaction Methods 0.000 claims description 21
- 229940126214 compound 3 Drugs 0.000 claims description 20
- 230000007062 hydrolysis Effects 0.000 claims description 20
- 239000002608 ionic liquid Substances 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 11
- -1 1-ethyl-3-methylimidazole diammonium nitrile Chemical class 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims description 8
- 229910001424 calcium ion Inorganic materials 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- QKWWDTYDYOFRJL-UHFFFAOYSA-N 2,2-dimethoxyethanamine Chemical compound COC(CN)OC QKWWDTYDYOFRJL-UHFFFAOYSA-N 0.000 claims description 7
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 claims description 7
- 238000002156 mixing Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 6
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 6
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 5
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 3
- 239000001110 calcium chloride Substances 0.000 claims description 3
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 238000007670 refining Methods 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims 3
- 239000007788 liquid Substances 0.000 claims 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 claims 1
- 239000000292 calcium oxide Substances 0.000 claims 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 239000012467 final product Substances 0.000 abstract description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 230000000171 quenching effect Effects 0.000 description 9
- XAXGEECGULRZGN-UHFFFAOYSA-N 1-(2,2-dimethoxyethyl)-5-methoxy-6-methoxycarbonyl-4-oxopyridine-3-carboxylic acid Chemical compound COC(OC)CN1C=C(C(O)=O)C(=O)C(OC)=C1C(=O)OC XAXGEECGULRZGN-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229940125782 compound 2 Drugs 0.000 description 7
- IBZJNLWLRUHZIX-UHFFFAOYSA-N 1-ethyl-3-methyl-2h-imidazole Chemical compound CCN1CN(C)C=C1 IBZJNLWLRUHZIX-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000011830 basic ionic liquid Substances 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- MVUMJYQUKKUOHO-AATRIKPKSA-N ethyl (e)-3-(dimethylamino)prop-2-enoate Chemical compound CCOC(=O)\C=C\N(C)C MVUMJYQUKKUOHO-AATRIKPKSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical class CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 229940124321 AIDS medicine Drugs 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000036436 anti-hiv Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000845 maltitol Substances 0.000 description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 2
- 229940035436 maltitol Drugs 0.000 description 2
- 235000010449 maltitol Nutrition 0.000 description 2
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 2
- 229960004742 raltegravir Drugs 0.000 description 2
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- VMSLCPKYRPDHLN-UHFFFAOYSA-N (R)-Humulone Chemical compound CC(C)CC(=O)C1=C(O)C(CC=C(C)C)=C(O)C(O)(CC=C(C)C)C1=O VMSLCPKYRPDHLN-UHFFFAOYSA-N 0.000 description 1
- KQIGMPWTAHJUMN-VKHMYHEASA-N 3-aminopropane-1,2-diol Chemical group NC[C@H](O)CO KQIGMPWTAHJUMN-VKHMYHEASA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- RRSGNBPOYMCOPK-UHFFFAOYSA-N CO[Ca] Chemical compound CO[Ca] RRSGNBPOYMCOPK-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229940099797 HIV integrase inhibitor Drugs 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- 229910018162 SeO2 Inorganic materials 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N anhydrous methyl chloride Natural products ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- AMJQWGIYCROUQF-UHFFFAOYSA-N calcium;methanolate Chemical compound [Ca+2].[O-]C.[O-]C AMJQWGIYCROUQF-UHFFFAOYSA-N 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical class NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000003084 hiv integrase inhibitor Substances 0.000 description 1
- 229940124524 integrase inhibitor Drugs 0.000 description 1
- 239000002850 integrase inhibitor Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- QGBPKJFJAVDUNC-UHFFFAOYSA-N methyl 4-methoxy-3-oxobutanoate Chemical compound COCC(=O)CC(=O)OC QGBPKJFJAVDUNC-UHFFFAOYSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000000135 prohibitive effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a preparation method of a dolutegravir key intermediate, which comprises the following steps: the invention provides a simple synthetic path, further optimizes the reaction condition, saves the reaction cost and improves the yield of a final product.
Description
Technical Field
The invention belongs to the technical field of organic synthesis pharmaceutical chemistry, and particularly relates to a preparation method of a dolutegravir key intermediate.
Background
1- (2, 2-dimethoxy ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid-2-methyl ester is an important intermediate for synthesizing novel anti-HIV/AIDS drug dolutegravir. The dolutegravir is an anti-AIDS integrase inhibitor approved by the American FDA in 2013, compared with the existing HIV integrase inhibitor, namely, raltegravir and etiquevir, the safety of the drug is improved, compared with the anti-HIV/AIDS drug, namely, raltegravir, of moxaeast, the dolutegravir not only achieves the curative effect comparable to that of the drug in a three-phase clinical test, but also does not need to be combined with a drug accelerator, has very strong drug resistance property, and the dosage is taken once daily.
At present, the synthesis of 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid-2-methyl ester mainly comprises two routes, one of which is taking maltol as a starting material. The protected maltitol is oxidized by SeO2 to obtain maltitol alpha-acid, which is then substituted by 3-aminopropane-1, 2-diol to obtain pyridone. The ester is obtained by methyl iodide treatment. Finally, carboxylation of pyridone intermediates (similar in structure to 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid-2-methyl ester) was synthesized in low yield under the catalysis of Pd (PPh 3) 4. This method requires a large number of synthesis steps and cumbersome chromatographic purification procedures, resulting in very low overall yields (5-10%). The other is chloridized by dienone in methanol/tetrahydrofuran, and then NaH is used for substitution synthesis of 4-methoxy methyl acetoacetate. Treatment of methyl 4-methoxyacetoacetate with N, N-dimethylformamide dimethyl acetal (DMFDMA) gives vinylamides, subsequent replacement by aminoacetaldehyde dimethyl acetal, and finally promotion of intermolecular ring closure by LiH followed by selective hydrolysis gives 2-methyl 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid. However, this route is cost prohibitive to raw materials and involves multiple hazardous reagents.
Disclosure of Invention
The invention aims to solve the defects in the prior art, and provides a preparation method of a dolutegravir key intermediate, which is realized by the following technical scheme:
the invention discloses a preparation method of a dolutegravir key intermediate, which comprises the following steps:
s1, mixing and dissolving 3- (N, N-dimethylamino) ethyl acrylate, pyridine and methyl oxalyl chloride by an organic solvent, regulating the reaction temperature to promote the reaction to be completed, and then extracting, washing, distilling under reduced pressure and refining to obtain a compound 1;
s2, mixing the compound 1 with aminoacetaldehyde dimethyl acetal and methyl bromoacetate for reaction to prepare a compound 3;
s3, dissolving the compound 3 in an alkaline ionic liquid, and carrying out intramolecular cyclization under the promotion of calcium ions to form a compound 4;
s4, hydrolyzing the compound 4 to finally obtain the dolutegravir key intermediate 1- (2, 2-dimethoxy ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid 2-methyl ester.
As a further improvement, the organic solvent in the step S1 is any one of pyridine, triethylamine, calcium methoxide and methoxy calcium, and the reaction temperature is kept at-5 ℃.
As a further improvement, in step S1 according to the present invention, ethyl 3- (N, N-dimethylamino) acrylate: the molar ratio of the methyl oxalyl chloride is 1:1.5.
by adopting the above technical scheme, the yield of Trimethylamine (TEA) or sodium methoxide is significantly reduced compared to pyridine, while the yield of the environment-friendly alkali sodium methoxide is higher, but a by-product (dimethyl oxalate) is detected from the reaction mixture. At the same time, the amount of the added methyl oxalyl chloride is excessive to 1.5 equivalent in order to consume the 3- (N, N-dimethylamino) fully. Experiments have also shown that lower temperatures (less than 5 ℃) prevent the reaction from proceeding, while higher temperatures (greater than 5 ℃) cause unwanted side reactions.
As a further improvement, the reaction temperature in the step S2 is maintained at 10-20 ℃.
As a further improvement, the alkaline ionic liquid in the step S3 is 1-ethyl-3-methylimidazole dicyano, and the mass ratio of the added alkaline ionic liquid to the compound 3 is 1.1-1.3:1.
The preferred basic ionic liquid in step S3 is 1-ethyl-3-methylimidazolium diammonium nitrile, and the mass ratio of basic ionic liquid to compound 3 is 1.2:1.
By adopting the technical scheme, the 1-ethyl-3-methylimidazole diammonium nitrile ionic liquid is added to dissolve the compound 3, if too little ionic liquid is added, the compound 3 cannot be completely dissolved, and if too much ionic liquid is added, the catalytic property of the ionic liquid can be weakened, and the reaction is inhibited.
As a further improvement, the reaction temperature of the reaction in the step S3 is maintained at-10-0 ℃.
As a further improvement, the reaction temperature of the reaction in the step S3 is maintained at-5 ℃.
As a further improvement, the calcium ion in the S3 is any one of calcium bromide, calcium chloride and calcium sulfate.
As a further improvement, in the step S4, any one of calcium hydroxide, potassium hydroxide and lithium hydroxide is selected for hydrolysis, and the hydrolysis temperature is maintained at-10 ℃.
As a further improvement, lithium hydroxide is selected for the hydrolysis, and the hydrolysis temperature is maintained at-5 ℃.
Preferably, the calcium ions in step S4 are provided using calcium bromide.
By adopting the technical scheme, experiments show that the product yield of the calcium bromide is highest.
Preferably, lithium hydroxide is used for the hydrolysis, and the hydrolysis temperature is maintained at-5 ℃.
The beneficial effects of the invention are as follows:
by adopting the technical scheme, although sodium hydroxide and potassium hydroxide are cheaper, the lithium hydroxide has low selectivity compared with lithium hydroxide in the actual hydrolysis process, and in addition, if the high temperature is kept in the hydrolysis process, the high selectivity can be damaged, but the hydrolysis reaction rate is obviously slowed down due to the too low temperature.
The invention has the advantages that after the compound 3 is synthesized, the compound 3 is dissolved by using the 1-ethyl-3-methylimidazole dicyanonitrile ionic liquid, the ionic liquid is used as a solvent and has certain reaction catalysis characteristics, the alkaline environment of the next reaction of the compound 3 is satisfied, the required reaction temperature is reduced, and meanwhile, the ionic liquid can be collected by filtration for recycling after the reaction is finished, so that the yield of the final product is greatly improved and reaches 68%.
Detailed Description
The technical scheme of the invention is further described by the following specific examples:
example 1
The embodiment 1 of the invention discloses a preparation method of a dolutegravir key intermediate, which comprises the following steps:
in a subzero 5℃environment, 284 g,2mol of ethyl 3- (N, N-dimethylamino) acrylate and 190g,2.4mol of pyridine were dissolved in 500ml of dichloromethane, and after stirring and mixing, a solution of 365 g,3mol of methyl oxalyl chloride in dichloromethane was poured. The reaction mixture was allowed to react at a temperature of 5 ℃ for 20 minutes under nitrogen protection, and then warmed to room temperature. After standing for two hours, quenching reaction was performed using 200ml of 5% sodium bicarbonate solution, and the organic phase was separated and washed with 100ml of purified water. After the solvent was distilled off under reduced pressure, a crude product was obtained. The crude product was then dissolved in methyl tert-butyl ether and heated to reflux, cooled to 50℃after the end of the reflux, stirred for 1 hour and cooled to-5 ℃. Immediately after solid precipitation, filtration and washing with cold methyl tert-butyl ether solution gave 218g of compound 1 after drying in 95% yield.
229g,1mol of Compound 1 were dissolved in 500ml of methanol at-15℃and 110g,1.05mol of aminoacetaldehyde dimethyl acetal were added during stirring. Then, 800ml of methyl bromoacetate and 130g of 1mol of N, N-diisopropylethylamine were poured again and stirred for 30 minutes to obtain 220g of compound 2. Compound 2 was dissolved in 242g of 1-ethyl-3-methylimidazole diammine basic ionic liquid, followed by addition of 40g of calcium bromide and warming to room temperature. Quenching reaction is carried out by saturated ammonium chloride solution. The organic phase was separated and distilled under reduced pressure to give compound 3 in 85% yield.
To the organic phase containing compound 3 was added 300ml of water. Cooled to below 0deg.C, 82g,2mol of lithium hydroxide aqueous solution was added. The reaction mixture was stirred and kept at 0 ℃ for 6 hours for hydrolysis. After the hydrolysis, hydrochloric acid is used for quenching reaction, methylene dichloride is added for extraction, and 5% sodium bicarbonate aqueous solution and 2% sodium chloride aqueous solution are used for washing the organic solvent to obtain a crude product. The crude product is added into isopropanol, cooled to minus 5 ℃ and filtered, the filtrate, especially the recovered alkaline ionic liquid, can be used together with the next raw material, and then washed and dried by isopropanol to obtain refined 64g of target product 1- (2, 2-dimethoxy ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid 2-methyl ester, and the yield is 68 percent.
Example 2
In a subzero 5℃environment, 284 g,2mol of ethyl 3- (N, N-dimethylamino) acrylate and 190g,2.4mol of pyridine were dissolved in 500ml of dichloromethane, and after stirring and mixing, 244g,2mol of a solution of methyl oxalyl chloride in dichloromethane was poured. The reaction mixture was allowed to react at a temperature of 5 ℃ for 20 minutes under nitrogen protection, and then warmed to room temperature. After standing for two hours, quenching reaction was performed using 200ml of 5% sodium bicarbonate solution, and the organic phase was separated and washed with 100ml of purified water. After the solvent was distilled off under reduced pressure, a crude product was obtained. The crude product was then dissolved in methyl tert-butyl ether and heated to reflux, cooled to 50℃after the end of the reflux, stirred for 1 hour and cooled to-5 ℃. Immediately after solid precipitation, filtration and washing with cold methyl tert-butyl ether solution gave 218g of compound 1 after drying in 95% yield.
229g,1mol of Compound 1 were dissolved in 500ml of methanol at-15℃and 110g,1.05mol of aminoacetaldehyde dimethyl acetal were added during stirring. Then, 800ml of methyl bromoacetate and 130g of 1mol of N, N-diisopropylethylamine were poured again and stirred for 30 minutes to obtain 220g of compound 2. Compound 2 was dissolved in 242g of 1-ethyl-3-methylimidazole diammine basic ionic liquid, followed by addition of 40g of calcium chloride and warming to room temperature. Quenching reaction is carried out by saturated ammonium chloride solution. The organic phase was separated and distilled under reduced pressure to give compound 3 in 85% yield.
To the organic phase containing compound 3 was added 300ml of water. Cooled to below 0deg.C, 82g,2mol of lithium hydroxide aqueous solution was added. The reaction mixture was stirred and kept at 0 ℃ for 6 hours for hydrolysis. After the hydrolysis, hydrochloric acid is used for quenching reaction, methylene dichloride is added for extraction, and 5% sodium bicarbonate aqueous solution and 2% sodium chloride aqueous solution are used for washing the organic solvent to obtain a crude product. The crude product is added into isopropanol, cooled to minus 5 ℃ and filtered, the filtrate, especially the recovered alkaline ionic liquid, can be used together with the next raw material, and then washed and dried by isopropanol to obtain refined 64g of target product 1- (2, 2-dimethoxy ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid 2-methyl ester, and the yield is 52 percent.
Example 3
In a subzero 5℃environment, 284 g,2mol of ethyl 3- (N, N-dimethylamino) acrylate and 190g,2.4mol of pyridine were dissolved in 500ml of dichloromethane, and after stirring and mixing, 244g,2mol of a solution of methyl oxalyl chloride in dichloromethane was poured. The reaction mixture was allowed to react at a temperature of 5 ℃ for 20 minutes under nitrogen protection, and then warmed to room temperature. After standing for two hours, quenching reaction was performed using 200ml of 5% sodium bicarbonate solution, and the organic phase was separated and washed with 100ml of purified water. After the solvent was distilled off under reduced pressure, a crude product was obtained. The crude product was then dissolved in methyl tert-butyl ether and heated to reflux, cooled to 50℃after the end of the reflux, stirred for 1 hour and cooled to-5 ℃. Immediately after solid precipitation, filtration and washing with cold methyl tert-butyl ether solution gave 218g of compound 1 after drying in 95% yield.
229g,1mol of Compound 1 were dissolved in 500ml of methanol at-15℃and 110g,1.05mol of aminoacetaldehyde dimethyl acetal were added during stirring. Then, 800ml of methyl bromoacetate and 130g of 1mol of N, N-diisopropylethylamine were poured again and stirred for 30 minutes to obtain 220g of compound 2. Compound 2 was dissolved in 242g of 1-ethyl-3-methylimidazole diammonium nitrile basic ionic liquid, followed by addition of 40g of calcium sulfate and warming to room temperature. Quenching reaction is carried out by saturated ammonium chloride solution. The organic phase was separated and distilled under reduced pressure to give compound 3 in 85% yield.
To the organic phase containing compound 3 was added 300ml of water. Cooled to below 0deg.C, 82g,2mol of lithium hydroxide aqueous solution was added. The reaction mixture was stirred and kept at 0 ℃ for 6 hours for hydrolysis. After the hydrolysis, hydrochloric acid is used for quenching reaction, methylene dichloride is added for extraction, and 5% sodium bicarbonate aqueous solution and 2% sodium chloride aqueous solution are used for washing the organic solvent to obtain a crude product. The crude product is added into isopropanol, cooled to minus 5 ℃ and filtered, the filtrate, especially the recovered alkaline ionic liquid, can be used together with the next raw material, and then washed and dried by isopropanol to obtain refined 64g of target product 1- (2, 2-dimethoxy ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridine dicarboxylic acid 2-methyl ester, and the yield is 31 percent.
Comparative example 1
This comparative example 1 is basically identical to example 1 except that:
the use of calcium ions to promote intramolecular cyclization while the use of 1-ethyl-3-methylimidazole diammonium nitrile basic ionic liquid as solvent resulted in a yield of compound 3 of only 55% resulting in a final product yield of 45%. Because of the existence of the 1-ethyl-3-methylimidazole dicyano ionic liquid, the reaction mixture can be ensured to completely react under the alkaline environment without excessively high temperature, and meanwhile, the ionic liquid also has good catalytic property, and can be reused after filtration and collection, and the yield of the final product is greatly improved when the ionic liquid is used together with the next raw material.
In summary, the invention provides a novel and efficient method for synthesizing dolutegravir intermediates. Compound 1 was synthesized in high yields using oxalyl methyl chloride and ethyl 3- (N, N-dimethylamine) acrylate as starting materials. Then adding aminoacetaldehyde dimethyl acetal and methyl bromoacetate for reaction, dissolving the obtained compound 2 in 1-ethyl-3-methylimidazole dicyano alkaline ionic liquid containing calcium ions, wherein the existence of the alkaline ionic liquid not only catalyzes the reaction of the mixture, but also reduces the reaction temperature, and can be recycled, and the intramolecular cyclization process of the compound 3 is smoothly carried out under the promotion of the alkaline ionic liquid and the calcium ions. The highly selective hydrolysis product, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid 2-methyl ester, was then successfully synthesized by treating compound 4 with lithium hydroxide. These results provide a simple route for the synthesis of dolutegravir intermediates and reduce the cost of synthesis.
Finally, it should also be noted that the above list is merely a specific example of the invention. Obviously, the invention is not limited to the above embodiment examples, but many variations are possible. All modifications directly derived or suggested to one skilled in the art from the present disclosure should be considered as being within the scope of the present invention.
Claims (3)
1. The preparation method of the dolutegravir key intermediate is characterized by comprising the following steps of:
s1, mixing and dissolving 3- (N, N-dimethylamino) ethyl acrylate, pyridine and methyl oxalyl through an organic solvent
Chlorine, adjusting reaction temperature to promote reaction, extracting, washing, distilling under reduced pressure, and refining to obtain
Compound 1;
s2, mixing the compound 1 with aminoacetaldehyde dimethyl acetal and methyl bromoacetate for reaction to prepare a compound 3;
s3, dissolving the compound 3 in alkaline ionic liquid, and forming a compound through intramolecular cyclization under the promotion of calcium ions
A substance 4;
s4, hydrolyzing the compound 4 to finally obtain a dolutegravir key intermediate 1- (2, 2-dimethoxy)
Ethyl) -1, 4-dihydro-3-methoxy-4-oxo-2, 5-pyridinedicarboxylic acid 2-methyl ester;
the organic solvent in the step S1 is methylene dichloride, and the reaction temperature is kept
At-5 to-5 ℃; in the step S1, 3- (N, N-dimethylamino) ethyl acrylate: mole of methyl oxalyl chloride
The molar ratio is 1:1.5; the reaction temperature in the step S2 is kept at 10-20 ℃; the base in the step S3
The sex ion liquid is 1-ethyl-3-methylimidazole diammonium nitrile, and the mass ratio of the basic ion liquid to the compound 3 is added
1.1-1.3:1; the reaction temperature of the reaction in the step S3 is maintained at-10-0 ℃; calcium in the S3
The ions are any one of calcium bromide, calcium chloride and calcium sulfate added into the system to form calcium ions; in the step S4, hydrogen is selected for hydrolysis
Any one of calcium oxide, potassium hydroxide and lithium hydroxide, and the hydrolysis temperature is maintained at-10 ℃ to-10 ℃.
2. The method for preparing a dolutegravir key intermediate as claimed in claim 1, wherein said S3
The reaction temperature of the reaction in the step was maintained at-5 ℃.
3. The process for preparing a dolutegravir key intermediate as claimed in claim 2, wherein the process comprises the steps of
Lithium hydroxide is selected for hydrolysis, and the hydrolysis temperature is maintained at-5 ℃.
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