CN106946935B - Preparation method of diastereoisomer nucleoside derivative - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 23
- 239000000843 powder Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- 239000000460 chlorine Substances 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 238000001953 recrystallisation Methods 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 11
- 238000005481 NMR spectroscopy Methods 0.000 claims description 10
- 238000004458 analytical method Methods 0.000 claims description 7
- 238000012544 monitoring process Methods 0.000 claims description 4
- 238000005070 sampling Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 239000011259 mixed solution Substances 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 abstract description 11
- 229960003560 tenofovir alafenamide fumarate Drugs 0.000 abstract description 5
- SVUJNSGGPUCLQZ-FQQAACOVSA-N tenofovir alafenamide fumarate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 SVUJNSGGPUCLQZ-FQQAACOVSA-N 0.000 abstract description 5
- 229910052736 halogen Inorganic materials 0.000 abstract description 4
- 150000002367 halogens Chemical class 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- 238000012512 characterization method Methods 0.000 description 12
- 125000001309 chloro group Chemical group Cl* 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 7
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- YMTWOALHGRUKJC-UHFFFAOYSA-N heptane methoxycyclopentane Chemical compound CCCCCCC.COC1CCCC1 YMTWOALHGRUKJC-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000004437 phosphorous atom Chemical group 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- MEJAFWXKUKMUIR-FHPNUNMMSA-N (e)-but-2-enedioic acid;propan-2-yl (2s)-2-[[[(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-phenoxyphosphoryl]amino]propanoate Chemical compound OC(=O)\C=C\C(O)=O.O([P@@](=O)(CO[C@H](C)CN1C2=NC=NC(N)=C2N=C1)N[C@@H](C)C(=O)OC(C)C)C1=CC=CC=C1 MEJAFWXKUKMUIR-FHPNUNMMSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ASJSAQIRZKANQN-CRCLSJGQSA-N 2-deoxy-D-ribose Chemical compound OC[C@@H](O)[C@@H](O)CC=O ASJSAQIRZKANQN-CRCLSJGQSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- BTOJSYRZQZOMOK-UHFFFAOYSA-N 4-chloro-7-(4-methylphenyl)sulfonylpyrrolo[2,3-d]pyrimidine Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N1C2=NC=NC(Cl)=C2C=C1 BTOJSYRZQZOMOK-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 229940126656 GS-4224 Drugs 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 229940123527 Nucleotide reverse transcriptase inhibitor Drugs 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 108020005202 Viral DNA Proteins 0.000 description 1
- IACQCQDWSIQSRP-ZCFIWIBFSA-N [(2r)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-[hydroxy(phosphonooxy)phosphoryl]oxyphosphinic acid Chemical compound N1=CN=C2N(C[C@@H](C)OCP(O)(=O)OP(O)(=O)OP(O)(O)=O)C=NC2=C1N IACQCQDWSIQSRP-ZCFIWIBFSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of diastereoisomeric compound I, said process comprising the steps of: heating and stirring the compound III in an organic solvent to convert the configuration of the compound III to obtain a compound I, wherein the X group is halogen; compared with the prior artThe preparation method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, few side reactions, high yield, small environmental pollution and suitability for industrial production, and provides a new way for preparing the key intermediate of tenofovir alafenamide fumarate.
Description
Technical Field
The invention relates to a preparation method of an intermediate of tenofovir alafenamide fumarate.
Background
Tenofovir alafenamide fumarate (Tenofovir alafenamide fumarate), which is chemically 9- [ (R) -2- [ [ (S) - [ [ (S) -1- (isopropoxycarbonyl) ethyl ] amino ] phenoxyphosphinyl ] methoxy ] propyl ] adenine fumarate, is a novel nucleotide reverse transcriptase inhibitor.
The compound was developed by Gilead Sciences, usa and marketed in 2015 in the united states for the treatment of adult HIV infection. The medicine is also used for treating hepatitis B and is currently in phase III clinic. The product is rapidly converted into tenofovir after being taken orally, is phosphorylated into tenofovir diphosphate under the action of cell kinase, and inhibits viral polymerase by being competitively combined with a natural deoxyribose substrate and causes the elongation termination of a DNA chain after being inserted into viral DNA, thereby inhibiting the activity of HIV and HBV.
The compound (I) (X is halogen) is an important intermediate for synthesizing tenofovir alafenamide fumarate, and the structure is shown as follows:
the phosphorus atom in the structure is a chiral center, so that I is composed of two diastereoisomers, and only compound III which is a racemate of compound I at the position of the phosphorus atom and has almost no diastereoisomer selectivity can be synthesized in the general literature (NUCLEOSIDES, NUCLEOTIDES & NUCLEIC ACIDS 2001,20, 621; WO2015/40640A 2; WO2015/107451A 2).
The known literature (U.S. Pat. No. 3, 2013/0090473, 1; WO 2013/052094, 2) discloses a conversion method, in which III is heated and reacted in one or a mixed solvent of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, acetonitrile, toluene, chlorobenzene, 1, 2-dichloroethane, 1, 4-dioxane, sulfolane and trichloroethylene to obtain I with high selectivity.
Disclosure of Invention
The invention provides a novel preparation method of a compound I with high diastereoisomer selectivity purity, which has the advantages of mild reaction conditions, less side reactions, high yield, small environmental pollution and suitability for industrial production.
To this end, the present invention provides a process for the preparation of diastereomeric compounds I, said process comprising the steps of:
heating and stirring the compound III in an organic solvent to convert the configuration thereof to obtain a compound I,
wherein the X group is halogen.
Wherein the X group is chlorine or bromine, the organic solvent is one or a combination of toluene, n-heptane and methyl cyclopentyl ether, and the volume mass ratio of the organic solvent to the compound III is 1-10000 ml: 1g, and the reaction temperature is 0-100 ℃.
Preferably, the volume mass ratio of the organic solvent to the compound III is 10-1000 ml: 1g, and the reaction temperature is 20-80 ℃.
More preferably, the volume mass ratio of the organic solvent to the compound III is 5-20 ml: 1g, and the reaction temperature is 60-75 ℃.
The invention also includes a process for the preparation of compound III, said process comprising the steps of: adding a halogenating reagent into the organic solvent of the compound II, heating to obtain a required compound III,
wherein the X group is halogen.
Wherein, the compound II is the prior art and can be prepared by self or purchased from the market.
The organic solvent is one or a combination of n-heptane and methyl cyclopentyl ether, and the volume mass ratio of the organic solvent to the compound II is 1-10000 ml: 1g, wherein the halogenating reagent is selected from thionyl chloride, oxalyl chloride, phosphorus trichloride, thionyl bromide, oxalyl bromide or phosphorus tribromide, and the molar ratio of the halogenating reagent to the compound II is 1-1000: 1, the reaction temperature is 0-100 ℃.
Preferably, the volume mass ratio of the organic solvent to the compound II is 10-1000 ml: 1g, the molar ratio of the halogenated reagent to the compound II is 1-100: 1, the reaction temperature is 20-80 ℃.
More preferably, the volume mass ratio of the organic solvent to the compound II is 5-20 ml: 1g, and the reaction temperature is 50-75 ℃.
Compared with the prior art, the method of the invention has the following beneficial effects: as shown in table one, wherein,
prior art 1 references are: nucloeosides, nucloetides & nucloeic ACIDS 2001,20, 621; WO2015/40640A 2; WO2015/107451A 2.
The prior art 2 documents are: US 2013/0090473 a 1;
table one:
Detailed Description
The invention is further illustrated by the following examples, which are not intended to be limiting.
Preparation of examples 1, III X is chlorine
II (100g) is dissolved in 1000mL of methyl cyclopentyl ether and placed in a 2L three-necked bottle, thionyl chloride (1L) is added under the protection of nitrogen, the reaction is heated to 60 ℃ for sixteen hours, TLC shows that the reaction is finished, and the solvent is directly evaporated to dryness to obtain 108g of III.
Characterisation data NMR (400MHz, CDCl)3):10.02(d,1H),9.47(d,1H),8.80(br,0.5H),8.42(s,0.5H),8.06(m,1H),7.03-7.45(m,5H),4.62(dd,0.5H),4.55(d,0.5H),4.23(m,2H),0.86(d,1.5H),0.81(d,1.5H)
Preparation of examples 2, III X is chlorine
The powder of II (100g) was suspended in 1000mL of methylcyclopentyl ether: the mixed solvent of n-heptane 1:1 is placed in a 2L three-neck flask, thionyl chloride (1L) is added under the protection of nitrogen, the mixture is heated to 70 ℃ for reaction for 12 hours, TLC shows that the reaction is finished, and the solvent is directly evaporated to dryness to obtain 104g of crude III.
Characterization data as in example 1
Example 3 preparation of I, X is chlorine and the solvent is methylcyclopentyl ether
Suspending the powder of III (100g) in methyl cyclopentyl ether (800ml) and placing in a 2L three-necked flask, heating to 70 ℃ and keeping the temperature, sampling every 2 hours, carrying out nuclear magnetic resonance analysis, monitoring the reaction progress until the I content is more than 95%, and reaching the I content more than or equal to 95% at 12 hours. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 80 g (80% yield) of I as a pure white solid powder.
Characterization data: NMR (400MHz, CDCl)3):10.02(d,1H),9.47(d,1H),8.80(br,1H),8.06(m,1H),7.03-7.45(m,5H),4.55(d,1H),4.23(m,2H),0.86(d,3H)
Example 4, preparation of I, X is chlorine, solvent is methylcyclopentyl ether III (98.0g) powder is suspended in methylcyclopentyl ether (1200ml) and placed in a 2L three-necked flask, heated to 70 ℃ and incubated, and samples are taken every 2 hours with NMR analysis to monitor the progress of the reaction until the I content is greater than 95% at 12 hours and is greater than or equal to 95% at 12 hours. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 85.3 g (87% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 5, preparation of I, X is chlorine, solvent is methylcyclopentyl ether III (101g) powder is suspended in methylcyclopentyl ether (2000ml) and placed in a 2L three-necked flask, heated to 70 ℃ and incubated, and samples are taken every 2 hours to monitor the progress of the reaction by NMR analysis until the I content is greater than 95% and at 24 hours it is greater than or equal to 95%. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 82.8 g (yield 82%) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 6, preparation of I, X is chloro, solvent is methylcyclopentyl ether: n-heptane 1:1 powder of III (103g) was suspended in methyl cyclopentyl ether n-heptane 1:1(1200ml) and placed in a 2L three neck flask, heated to 70 ℃ and held at temperature, and sampled every 2 hours to monitor the progress of the reaction by nmr analysis until the I content was greater than 95% at 12 hours and was equal to or greater than 95% at 12 hours. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 94.8 g (92% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 7, preparation of I, X is chloro, solvent is methylcyclopentyl ether: n-heptane 1:2 powder of III (99.0g) was suspended in methylcyclopentyl ether 1:2(1200ml) and placed in a 2L three-necked flask, heated to 70 degrees celsius and incubated, and samples were taken every 2 hours at intervals for nmr analysis to monitor the progress of the reaction until the I content was greater than 95%, and at 24 hours until the I content was greater than or equal to 95%. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 71.3 g (72% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 8, preparation of I, X is chloro, solvent is methylcyclopentyl ether: n-heptane 2:1 powder of III (97.0g) was suspended in methyl cyclopentyl ether n-heptane 2:1(1200ml) and placed in a 2L three-necked flask, heated to 70 ℃ and incubated, and samples were taken every 2 hours for nmr analysis to monitor the progress of the reaction until the I content was greater than 95% and at 18 hours until the I content was greater than or equal to 95%. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 79.5 g (82% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 9, preparation of I, X is chlorine, solvent n-heptane powder of III (102.0g) was suspended in n-heptane (1200ml) and placed in a 2L three neck flask, heated to 70 ℃ and incubated, and samples were taken every 2 hours interval for NMR analysis to monitor the progress of the reaction until the I content was greater than 95% and at 36 hours it was > 95%. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 66.3 g (65% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 10 preparation of I, X is chlorine and the solvent is methylcyclopentyl ether
The powder of III (105g) was suspended in methylcyclopentyl ether (1200ml) and placed in a 2L three-necked flask, heated to 60 ℃ and held at temperature, and sampled every 2 hours with NMR analysis to monitor the progress of the reaction until the I content was greater than 95% and at 24 hours the I content was greater than or equal to 95%. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 86.0 g (82% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Example 11 preparation of I, X is chlorine and the solvent is methylcyclopentyl ether
Suspending the powder of III (96g) in methyl cyclopentyl ether (1200ml) and placing in a 2L three-necked flask, heating to 80 ℃ and keeping the temperature, sampling every 2 hours, carrying out nuclear magnetic resonance analysis, monitoring the reaction progress until the I content is more than 95%, and reaching the I content more than or equal to 95% at the 8 th hour. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 68.2 g of I as a pure white solid powder (71% yield).
Characterization data are as for example 3.
Example 12 preparation of I, X is chlorine and the solvent is toluene
Suspending the powder of III (105g) in toluene (1200ml) and placing in a 2L three-necked flask, heating to 70 ℃ and keeping the temperature, sampling at intervals of 2 hours, carrying out nuclear magnetic resonance analysis, and monitoring the reaction progress until the I content is more than 95%, and reaching the I content more than or equal to 95% at 72 hours. The solvent was directly evaporated to dryness to give crude I, purified with dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 65.0 g (62% yield) of I as a pure white solid powder.
Characterization data are as for example 3.
Claims (1)
1. A process for the preparation of diastereoisomeric compounds I,
wherein the X group is chlorine, characterized in that the method comprises the following steps: suspending 103g of compound III powder in 1200ml of a mixed solution of methyl cyclopentyl ether and n-heptane with a volume ratio of 1:1, placing the mixture in a 2L three-necked bottle, heating to 70 ℃, keeping the temperature, sampling at intervals of 2 hours, carrying out nuclear magnetic resonance analysis, monitoring the reaction progress until the ratio of I is more than 95%, and when the ratio of I is more than or equal to 95% at 12 hours, directly evaporating the solvent to obtain a crude product of I, and adding dichloromethane: recrystallization from 1: 1800 mL of n-heptane gave 94.8 g of a pure white solid powder.
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