CN108640856B - Asymmetric synthesis method of escitalopram intermediate and intermediate thereof - Google Patents
Asymmetric synthesis method of escitalopram intermediate and intermediate thereof Download PDFInfo
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- WSEQXVZVJXJVFP-FQEVSTJZSA-N escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 title claims abstract description 35
- 229960004341 escitalopram Drugs 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 18
- 238000011914 asymmetric synthesis Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000011925 1,2-addition Methods 0.000 claims abstract description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 11
- 239000003446 ligand Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 claims description 4
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 claims description 4
- 229940045803 cuprous chloride Drugs 0.000 claims description 4
- 229910021590 Copper(II) bromide Inorganic materials 0.000 claims description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
- SFJMFSWCBVEHBA-UHFFFAOYSA-M copper(i)-thiophene-2-carboxylate Chemical compound [Cu+].[O-]C(=O)C1=CC=CS1 SFJMFSWCBVEHBA-UHFFFAOYSA-M 0.000 claims description 2
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 229960003280 cupric chloride Drugs 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 14
- 238000003786 synthesis reaction Methods 0.000 description 14
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 229960001653 citalopram Drugs 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- WSEQXVZVJXJVFP-UHFFFAOYSA-N 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro-2-benzofuran-5-carbonitrile Chemical compound O1CC2=CC(C#N)=CC=C2C1(CCCN(C)C)C1=CC=C(F)C=C1 WSEQXVZVJXJVFP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- 108060003345 Adrenergic Receptor Proteins 0.000 description 1
- 102000017910 Adrenergic receptor Human genes 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 102000004300 GABA-A Receptors Human genes 0.000 description 1
- 108090000839 GABA-A Receptors Proteins 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- BEOKBUHJDGJDKO-UHFFFAOYSA-N [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 Chemical compound [Cl].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BEOKBUHJDGJDKO-UHFFFAOYSA-N 0.000 description 1
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 description 1
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses an asymmetric synthesis method of an escitalopram intermediate, which comprises the following steps of firstly, taking a compound (2) and a compound (3) as initial raw materials, and carrying out asymmetric 1, 2-addition reaction to obtain the escitalopram intermediate compound (1), wherein the reaction formula is as follows:
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of an escitalopram intermediate and an intermediate thereof.
Background
Escitalopram (common name: Escitalopram; trade name: cipalex), chemical name 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) -1, 3-dihydroisobenzofuran-5-carbonitrile. Molecular weight of escitalopram: 414.43, respectively; CAS accession number: 128196-01-0; the structural formula is shown as formula 1:
escitalopram was developed by Lundbeek corporation and first marketed in the uk in 7 months 2002. Escitalopram is a selective 5-hydroxytryptamine (5-HT) inhibitor, is a derivative of the antidepressant drug citalopram (S-citalopram racemate), and has the activity of enhancing the 5-hydroxytryptamine performance of the central nervous system through the inhibition of 5-HT reuptake. Animal experiments show that the escitalopram is a high-selectivity 5-HT reuptake inhibitor and is applied to norkidneyAdenophrine and dopamine on glands had little effect. Escitalopram inhibits 5-HT reuptake 100 times as much as R-citalopram. Animal experiments show that the long-term administration of the medicine has no tolerance. Escitalopram has no or almost no affinity for 5-HT receptors (5-HTl-7), alpha and beta-adrenergic receptors, dopamine receptors (D1-5), histamine receptors (Hl-3), M receptors (Ml-5) and benzodiazepine receptors. Escitalopram for various ion channels (Na)+、K+、Cl-、Ca2 +) There is little or no affinity. It is generally believed that the anti-M, H and adrenergic receptors are associated with side effects of anticholinergic drugs, sedatives and cardiovascular drugs.
Prior patent documents: AU 8936295; EP 0347066; JP 1990036177; JP 1999292867; US 4943590. Non-patent documents: curr Med Res Opin.26(12): 2757-64; anals of Internal medicine.155(11): 772-85; the synthesis process of the escitalopram intermediate is introduced, but in the prior art, the synthesis process of the escitalopram intermediate has the defects of long route, high cost, low product yield and poor quality, and cannot be suitable for industrial mass production.
Disclosure of Invention
The purpose of the invention is as follows: aiming at the problems in the prior art, the invention provides an asymmetric synthesis method of an escitalopram intermediate, which has the advantages of high synthesis yield, good product purity and the like.
The invention also provides an escitalopram intermediate compound (1), and the escitalopram intermediate compound (1) provides a new raw material for escitalopram synthesis.
The technical scheme is as follows: in order to achieve the above object, according to the asymmetric synthesis method of escitalopram intermediate disclosed by the invention, compound (2) and compound (3) are used as starting materials, and are subjected to asymmetric 1, 2-addition reaction to obtain escitalopram intermediate compound (1), wherein the reaction formula is as follows:
preferably, the solvent for asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is one or more selected from the group consisting of anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous methyl tert-butyl ether, anhydrous dichloromethane, anhydrous toluene, anhydrous tert-butyl ether, anhydrous 2-methyltetrahydrofuran and anhydrous acetonitrile.
Preferably, the reaction temperature of the compound (2) and the compound (3) by the asymmetric 1, 2-addition reaction is-20 ℃ to 60 ℃.
Preferably, the chiral ligand used in the asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is selected from one or more of the following T005-T006,
preferably, the catalyst used for asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is one or more selected from copper chloride, cuprous chloride, cupric bromide, cuprous bromide, cupric iodide, CuTC, cupric cyanide and CuBr-SMe 2.
Further, the molar ratio of the compound (3) to the compound (2) is 1: 1-1.5: 1.
further, the molar ratio of the catalyst to the chiral ligand is 1: 1-1.2.
Further, the molar ratio of the catalyst to the compound (2) is 1: 20-200.
The escitalopram intermediate compound (1) synthesized by the asymmetric synthesis method of the escitalopram intermediate has the structural formula:
wherein, the compound (2) is synthesized by firstly reacting the compound (7) with Ls-BuLi and adding dry ice to generate a compound (6); adding a triphenylphosphine and chlorine compound into the compound (6) to react to generate a compound (4), adding a compound (2) obtained by reacting cuprous chloride with the compound (5) into the compound (4), wherein the synthetic route is as follows:
has the advantages that: compared with the prior art, the invention has the following advantages: compared with the defects of more steps, complex synthesis process and the like of an escitalopram intermediate in the prior art, the method has the advantages of novel synthesis route, simplicity, practicability, lower cost, high synthesis yield, higher yield, good product purity, cheap and easily-obtained raw materials, suitability for industrial production and the like, and the synthesized escitalopram intermediate provides a new intermediate raw material for the preparation of escitalopram.
Detailed Description
The present invention will be further described with reference to the following examples.
The method for detecting the purity of the escitalopram intermediate by HPLC comprises the following steps:
the test instrument: agilent 1100 high performance liquid chromatograph (DAD detector).
Chromatographic conditions are as follows: OD-H (4.6X 250mm, 5 μm) was used as a column, and the flow rate: 0.5 ml/min.
Mobile phase A: isopropyl alcohol; mobile phase B: n-heptane
The linear gradient elution was performed as follows:
| time (minutes) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 1 | 99 |
| 30 | 5 | 95 |
| 50 | 25 | 75 |
| 60 | 45 | 55 |
Ultraviolet detection wavelength: 210 nm.
Example 1
Synthesis of Compound (6)
Under the protection of nitrogen gas, 1.0kg (5mol) of compound (7) was added to 5L of anhydrous tetrahydrofuran in a 10L four-necked reaction flask at-30 ℃, 2L s-BuLi (2.5M tetrahydrofuran solution) was slowly added thereto, 250g of dry ice was added thereto after stirring for half an hour, the mixture was slowly warmed to room temperature after stirring for 1 hour, the pH was adjusted to about 6.5 with 15% acetic acid, and the mixture was filtered and dried to obtain 1.2kg (4.89mol) of compound (6), with the yield of 97.8% and the purity of 98.1%.
[M+H]+＝250
Synthesis of Compound (4)
1.2kg (4.89mol) of the compound (6) was added to 6L of methylene chloride in a 10L four-necked reaction flask at 0 ℃ and 1.67kg (5mol) of triphenylphosphine-chlorine complex was slowly added thereto, and the reaction was monitored by TLC, and the reaction was terminated after 12 hours, filtered, and the filtrate was used directly for the next reaction.
Synthesis of Compound (2)
Under the protection of nitrogen and at the temperature of-20 ℃, adding 5g of cuprous chloride (50mmol) into the filtrate, slowly adding 2L of the compound (5) (2.5M dichloromethane solution), monitoring the reaction by TLC, slowly raising the temperature to room temperature after 16 hours of reaction, adjusting the pH to be about 6.8 by using 15% acetic acid, filtering, concentrating the filtrate under reduced pressure to obtain a crude product of the compound (2), recrystallizing the crude product by using ethyl acetate/petroleum ether to obtain 1.46kg (4.58mol) of a refined product of the compound (2), wherein the yield is 93.7%, and detecting the purity by HPLC: the purity was 97.2%.
[M+H]+＝319
Example 2
Preparation of Compound (1)
Under the condition of-20 ℃, under the protection of nitrogen, 4.4L (2.5M tetrahydrofuran solution) of the compound (3) is added into a 20L reaction kettle, 5L of anhydrous dichloromethane is added into a reaction solvent, and a catalyst CuBr-SMe is added221g (0.1mol) and chiral ligand T00681 g (0.1mol), stirring for 1 hour, slowly adding 3.18kg (10.0mol) of compound (2) in 5L of anhydrous dichloromethane, TLC monitoring the reaction, finishing the reaction after 12 hours, heating to room temperature, slowly pouring into 10L of 5% acetic acid aqueous solution, separating, extracting the aqueous phase twice by dichloromethane, combining organic phases, concentrating the organic phase under reduced pressure to obtain a crude compound (1), recrystallizing the crude compound by methanol/water to obtain 3.28kg (9.59mol) of a refined product, wherein the molar yield is 95.9%, and the purity is detected by HPLC: 99.5 percent.
1H NMR(400MHz,DMSO-d6)δ7.88(s,1H),7.70–7.39(m,4H),7.29–6.97(m,2H),5.81(m,1H),4.99(m,1H),2.97–2.49(m,2H),2.49–2.29(m,1H),2.22(d,J＝9.4Hz,6H),2.18–1.95(m,3H),1.77–1.33(m,2H).
ESI+[M+H]+＝343.
Example 3
The synthesis procedure of example 1 was followed, except that: the reaction temperature was 20 ℃, the reaction solvent tetrahydrofuran was replaced with anhydrous dichloromethane, the catalyst was replaced with cuprous bromide (0.1mol), the chiral ligand was replaced with T005(0.12mol), compound (3) (20mol) and compound (2) (20 mol). The molar yield of the compound (1) is 95.1%, and the purity by HPLC test is: 98.8 percent.
Example 4
The synthesis procedure of example 1 was followed, except that: the reaction temperature is 60 ℃, the reaction solvent tetrahydrofuran is replaced by anhydrous toluene, the catalyst is replaced by copper chloride (0.1mol), the chiral ligand is replaced by T007(0.12mol), and the compound (3) (3mol) and the compound (2) (2 mol). Compound (1) in a molar yield of 96.4%, purity by HPLC: 97.5 percent.
Example 5
The synthesis procedure of example 1 was followed, except that: the reaction temperature is 30 ℃, the reaction solvent tetrahydrofuran is replaced by 2-methyltetrahydrofuran, the catalyst is replaced by copper bromide (0.08mol), the chiral ligand is replaced by T008(0.09mol), and the compound (3) (12mol) and the compound (2) (8 mol). The molar yield of the compound (1) was 94.5%, and the purity by HPLC was: 98.5 percent.
Example 6
Example 5 the procedure of example 4 was followed except that the reaction solvent was tetrahydrofuran in an equal volume and mixed with 2-methyltetrahydrofuran; the catalyst is prepared by mixing copper bromide and cuprous bromide in equal molar ratio, and the chiral ligand is the mixture of T006 and T008 in equal molar ratio.
Claims (3)
1. The asymmetric synthesis method of the escitalopram intermediate is characterized in that a compound (2) and a compound (3) are used as starting materials, and an asymmetric 1, 2-addition reaction is carried out to obtain the escitalopram intermediate compound (1), wherein the reaction formula is as follows:
the chiral ligand used in the asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is selected from one or more of the following T005-T006,
the catalyst used for the asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is selected from one or more of cupric chloride, cuprous chloride, cupric bromide, cuprous bromide, cupric iodide, CuTC, cupric cyanide and CuBr-SMe 2;
the molar ratio of the compound (3) to the compound (2) is 1: 1-1.5: 1; the molar ratio of the catalyst to the chiral ligand is 1: 1-1.2; the molar ratio of the catalyst to the compound (2) is 1: 20-200.
2. The asymmetric synthesis method of escitalopram intermediate according to claim 1, wherein the solvent for asymmetric 1, 2-addition reaction of compound (2) and compound (3) is one or more selected from the group consisting of anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous methyl tert-butyl ether, anhydrous dichloromethane, anhydrous toluene, anhydrous tert-butyl ether, anhydrous 2-methyltetrahydrofuran and anhydrous acetonitrile.
3. The asymmetric synthesis method of escitalopram intermediate according to claim 1, wherein the reaction temperature of the asymmetric 1, 2-addition reaction of the compound (2) and the compound (3) is-20 ℃ to 60 ℃.
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