CN113307812B - Preparation method of broad-spectrum tumor drug erlotinib - Google Patents
Preparation method of broad-spectrum tumor drug erlotinib Download PDFInfo
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- CN113307812B CN113307812B CN202110744086.9A CN202110744086A CN113307812B CN 113307812 B CN113307812 B CN 113307812B CN 202110744086 A CN202110744086 A CN 202110744086A CN 113307812 B CN113307812 B CN 113307812B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 239000005551 L01XE03 - Erlotinib Substances 0.000 title abstract description 5
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 title abstract description 5
- 229960001433 erlotinib Drugs 0.000 title abstract description 5
- 206010028980 Neoplasm Diseases 0.000 title description 9
- 229940079593 drug Drugs 0.000 title description 4
- 239000003814 drug Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 239000011701 zinc Substances 0.000 claims description 6
- 229910052725 zinc Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- XDPCNPCKDGQBAN-UHFFFAOYSA-N 3-hydroxytetrahydrofuran Chemical compound OC1CCOC1 XDPCNPCKDGQBAN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000085 borane Inorganic materials 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 3
- DPSTYIOIVSHZRI-UHFFFAOYSA-N pyrrolidin-3-one;hydrochloride Chemical compound Cl.O=C1CCNC1 DPSTYIOIVSHZRI-UHFFFAOYSA-N 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group 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
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- QGKLPGKXAVVPOJ-UHFFFAOYSA-N pyrrolidin-3-one Chemical compound O=C1CCNC1 QGKLPGKXAVVPOJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002210 biocatalytic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002761 liquid phase assay Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention relates to a preparation method of erlotinib, which is characterized in that a compound shown in a formula II is selectively reduced to obtain a compound shown in a formula I. The invention provides a preparation method of larotinib, which has the advantages of mild reaction conditions, high chiral selectivity, high product yield and suitability for commercial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of larotinib.
Background
The larotinib is developed by Loxo Oncology company, and is used as a broad-spectrum tumor drug for all tumor patients expressing TRK, but not for tumors at a certain anatomical position. TRK fusions are widely distributed in many cancers and affect all ages, while being genetically unrelated to tumors. Erlotinib has been shown to have a long lasting anti-tumor activity and good tolerability in Trk fusion cancers of a wide range of ages and tumor types.
The structure of the larotinib is shown as formula I:
disclosure of Invention
The invention provides a synthetic method of erlotinib, which comprises the following steps of selectively reducing a compound shown in a formula II to obtain a compound shown in a formula I,
wherein the selective reduction method is selected from biocatalytic asymmetric reduction or chemical asymmetric reduction.
Preferably, the selective reduction method is selected from the group consisting of chiral reduction reagent reduction or chiral catalytic hydrogenation reduction.
Preferably, the compound of formula II is selectively reduced with a borane reagent to provide the compound of formula I, the reaction solvent being selected from the group consisting of ethereal solvents, more preferably 2-methyltetrahydrofuran.
Preferably, the borane reagent is selected from zinc borohydride.
Preferably, S-3-hydroxytetrahydrofuran can be added in the reaction to improve the chiral selectivity of the reaction.
Preferably, the preparation method of the compound of the formula II comprises the following steps: reacting the compound 1 with 3-pyrrolidone or 3-pyrrolidone hydrochloride to obtain a compound 2, and reacting the compound 2 with the compound 3 to obtain a compound shown in a formula II;
wherein X is selected from chlorine, bromine or iodine;
in the present invention, compound 3, having an optical purity of greater than 99.9%, is used to prepare compounds of formula ii. The compound 3 is used for preparing the compound shown in the formula II without racemization and chiral configuration conversion. The invention relates to the detection of optical purity, which is to measure the optical purity generated after asymmetric carbonyl reduction of a compound shown in a formula II.
The liquid phase assay conditions for the compounds of formula I are as follows:
chiral enantiomeric assay chromatographic conditions: daicel Chiralpak IA, 5 μm, 250 × 4.6 mm; mobile phase: n-hexane: ethanol 99: 5; detection wavelength: 254 nm; flow rate: 0.8 mL/min; column temperature: at 25 ℃.
Compared with the prior art, the preparation method has the advantages of mild reaction conditions, high chiral selectivity, high product purity and high yield, and is suitable for commercial production.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to specific examples. The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the invention.
Example 1
42.64g of the compound shown in the formula II is added into 400ml of 2-methyltetrahydrofuran, 11.1g of zinc borohydride is added to react for 3 hours at 50-60 ℃, after the reaction is finished, the reaction solvent is recovered by decompression concentration, 250ml of ethanol is added into the residue to be dissolved, the ethanol is taken to dissolve the clear liquid, 350ml of methyl tert-butyl ether is added, the mixture is stirred at 20-30 ℃ to separate out solid, the solid is filtered and dried in vacuum, and 40.7g of the compound shown in the formula I is obtained, the yield is 95%, the purity is 99.5%, and the enantiomeric excess percentage ee% is 95.1%.
1HNMR(300MHz,d6DMSO)：9.12(d,J＝7.21Hz,1H),8.72(s,1H),8.77(s,1H),8.10(d,J＝7.2Hz,1H),6.80-7.31(m,3H),4.17(m,1H),4.03(m,1H),3.61(m,2H),3.47(m,2H),1.76-2.85(m,8H)；MS:(ESI,m/z,429.18,M+H)。
Example 2
42.64g of the compound shown in the formula II is added into 400ml of 2-methyltetrahydrofuran, 4g of S-3-hydroxytetrahydrofuran is added, 11.1g of zinc borohydride is added to react for 3 hours at 50-60 ℃, after the reaction is finished, the reaction solvent is recovered by decompression and concentration, 250ml of ethanol is added into the residue to dissolve, the ethanol is taken to dissolve clear liquid, 350ml of methyl tert-butyl ether is added, the mixture is stirred at 20-30 ℃ to separate out solid, the solid is filtered and dried in vacuum, and 40.4g of the compound shown in the formula I is obtained, the yield is 94.5%, the enantiomeric excess percentage ee% is 99.7%, and the purity is 99.6%. MS (ESI, M/z,429.16, M + H);1HNMR data was also essentially the same as in example 1.
Example 3
Adding 42.64g of a compound shown in the formula II into 250ml of ethanol, adding 11.1g of zinc borohydride, reacting for 3 hours at 50-60 ℃, adding 350ml of methyl tert-butyl ether after the reaction is finished, stirring at 20-30 ℃ to separate out solid, filtering, and drying in vacuum to obtain 40.1g of the compound shown in the formula I, wherein the yield is 93.6%, and the ee% of the enantiomeric excess percentage is 13.2%; product of1The HNMR data are also essentially the same as in example 1.
Example 4
Adding 42.64g of a compound shown in the formula II into 250ml of ethanol, adding 4g of S-3-hydroxytetrahydrofuran, adding 11.1g of zinc borohydride, reacting at 50-60 ℃ for 3 hours, adding 350ml of methyl tert-butyl ether after the reaction is finished, stirring at 20-30 ℃ to separate out a solid, filtering, and drying in vacuum to obtain 39.4g of a compound shown in the formula I, wherein the yield is 91.9%, and the enantiomeric excess percentage ee% is 15.2%; product of1The HNMR data are also essentially the same as in example 1.
EXAMPLE 5 preparation of starting Material
Adding the compound 1(66.7g), 25.5g of 3-pyrrolidone hydrochloride and 300ml of ethanol into a reaction bottle, adding 27.6g of potassium carbonate, reacting at 20-30 ℃ for 6-7 hours, filtering after the reaction is finished, concentrating the filtrate under reduced pressure to 100ml, adding 300ml of methyl tert-butyl ether, stirring to separate out a solid, filtering, and drying a filter cake in vacuum to obtain a compound 2(49.2g), wherein the yield is 88%; MS (ESI, M/z,280.05, M + H).
Adding a compound 2(29.6g, 106mmol), a compound 3(18g, 98.2mmol) and ethanol (200mL) into a reaction flask, dropwise adding N, N-diisopropylethylamine (16.5g, 128mmol), keeping the reaction temperature within 30 ℃, continuing to react for 5-8 hours after dropwise adding, controlling by TLC, adding methyl tert-butyl ether (300mL) after the reaction is finished, separating out solids, continuing to stir for 30 minutes, filtering, and drying a filter cake in vacuum to obtain 40.2g of a compound shown in a formula II, wherein the yield is 89%; MS (ESI, M/z,427.17, M + H).
Claims (3)
1. A process for the preparation of a compound of formula I, characterized in that a compound of formula II is selectively reduced with a borane reagent to give a compound of formula I,
wherein the borane reagent is selected from zinc borohydride, and the reaction solvent is selected from 2-methyltetrahydrofuran.
2. The process of claim 1, wherein S-3-hydroxytetrahydrofuran is further added to the reaction.
3. The process of claim 1, wherein compound 1 is reacted with 3-pyrrolidone or 3-pyrrolidone hydrochloride to provide compound 2, and compound 2 is reacted with compound 3 to provide a compound of formula ii;
wherein X is selected from chlorine, bromine or iodine;
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| CN113307812B true CN113307812B (en) | 2022-07-22 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107987082A (en) * | 2017-11-14 | 2018-05-04 | 苏州东南药业股份有限公司 | A kind of Preparation Method And Their Intermediate of Larotrectinib |
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| ES2543643T3 (en) * | 2011-03-10 | 2015-08-20 | Zach System S.P.A. | Asymmetric reduction process |
| CN111362949B (en) * | 2017-12-22 | 2021-12-21 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrazolo [1,5-a ] pyrimidine compound, and pharmaceutical composition and application thereof |
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| CN107987082A (en) * | 2017-11-14 | 2018-05-04 | 苏州东南药业股份有限公司 | A kind of Preparation Method And Their Intermediate of Larotrectinib |
Non-Patent Citations (2)
| Title |
|---|
| A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure a-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones;Gerald Pattenden et al.;《Org. Biomol. Chem.》;20080716;第6卷;第3432页Scheme 4及3436页右栏最后一段 * |
| 酮的不对称还原的研究进展;叶向阳 等;《精细石油化工》;54-59;19951231(第2期);第54-59页 * |
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