CN109422671B - Preparation method of apremilast intermediate - Google Patents
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- BXUJVINGXQGNFD-UHFFFAOYSA-N 1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethanamine Chemical compound CCOC1=CC(C(N)CS(C)(=O)=O)=CC=C1OC BXUJVINGXQGNFD-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 68
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- VAMZHXWLGRQSJS-UHFFFAOYSA-N 3-ethoxy-4-methoxybenzaldehyde Chemical compound CCOC1=CC(C=O)=CC=C1OC VAMZHXWLGRQSJS-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000012043 crude product Substances 0.000 claims abstract description 14
- 239000012065 filter cake Substances 0.000 claims abstract description 12
- 239000010410 layer Substances 0.000 claims abstract description 12
- 239000012044 organic layer Substances 0.000 claims abstract description 12
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 8
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 4
- 150000002642 lithium compounds Chemical class 0.000 claims abstract description 4
- 238000004537 pulping Methods 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 229910015900 BF3 Inorganic materials 0.000 claims description 5
- 150000002900 organolithium compounds Chemical class 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000010189 synthetic method Methods 0.000 abstract 1
- 230000001276 controlling effect Effects 0.000 description 20
- 238000001816 cooling Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 8
- 229910003002 lithium salt Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- -1 imine lithium salt Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- ANUZKYYBDVLEEI-UHFFFAOYSA-N butane;hexane;lithium Chemical compound [Li]CCCC.CCCCCC ANUZKYYBDVLEEI-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- 159000000002 lithium salts Chemical class 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229960001164 apremilast Drugs 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- XTIINWPNAMHVDG-UHFFFAOYSA-N 3-ethoxy-4-methoxybenzonitrile Chemical compound CCOC1=CC(C#N)=CC=C1OC XTIINWPNAMHVDG-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 1
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 238000010364 biochemical engineering Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide 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
- C07F7/10—Compounds having one or more C—Si linkages containing nitrogen having a Si-N linkage
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing an apremilast intermediate 1- (3-ethoxy-4-methoxy) phenyl-2-methylsulfonylethylamine (I), which comprises the following steps:
Description
Technical Field
The invention belongs to the field of pharmaceutical biochemical engineering, and particularly relates to a preparation method of an apremilast intermediate 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine.
Background
The CAS number of Apremilast (Apremilast) is 608141-41-9, the chemical name is (S) -2- [1- (3-ethoxy-4-methoxyphenyl) -2-methylsulfonylethyl ] -4-acetylaminoisoindoline-1, 3-dione, the compound is a novel small molecule oral medicine of a phosphodiesterase (PDE-4) inhibitor class developed by the American biopharmaceutical Corporation (Gelgene Corporation), inhibits the activity of a plurality of inflammatory markers involved in the pathogenesis of psoriasis, and the compound plays a role by regulating the action network of intracellular proinflammatory and anti-inflammatory factors, and can effectively treat the psoriatic arthritis.
1- (3-ethoxy-4-methoxy) phenyl-2-methanesulfonylethylamine (I) is a key intermediate for the preparation of apremilast. The synthesis of the compound is researched at home and abroad.
The synthesis method is reported for the first time in European patent EP 1126839.
The synthesis route takes 3-ethoxy-4-methoxybenzaldehyde as a raw material, hexamethyldisilazane-based lithium amide as an amino donor, and the hexamethyldisilazane-based lithium amide is condensed with dimethyl sulfone under the action of n-butyl lithium to prepare the compound (I), and the yield is 39% reported in literature, so that the optimization and promotion space is provided.
The original company has improved the synthetic route in patent WO 2012083153.
The synthetic route takes 3-ethoxy-4-methoxybenzaldehyde as a raw material, 3-ethoxy-4-methoxybenzonitrile is prepared through condensation and dehydration, and then an intermediate 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine is prepared under a system of n-butyl lithium and dimethyl sulfone, so that the yield of the route is high, but the route is long.
The following synthetic route is reported in patent WO2015181249a 1.
The method has the defects of more dimer impurities, incapability of refining, incomplete addition reaction, lower yield and harsh conditions, and is not suitable for large-scale industrial production.
Although there are many studies on the synthesis of 1- (3-ethoxy-4-methoxy) phenyl-2-methylsulfonylethylamine, there are some limitations, such as harsh reaction conditions, expensive reagents, low yield, etc.
Disclosure of Invention
The invention aims to provide a method for preparing 1- (3-ethoxy-4-methoxy) phenyl-2-methylsulfonyl ethylamine (I), which is characterized in that a feeding mode and a feeding ratio are changed on the basis of a synthesis method reported by the original research company for the first time, so that the controllable reaction condition and strong operability are realized, and the method is favorable for large-scale industrial production.
In order to solve the technical problem, the invention provides a preparation method of an apremilast intermediate shown as a formula (I), which comprises the following steps:
(a) adding dimethyl sulfone into a proper solvent, and reacting with an organic lithium compound at a temperature of-40-10 ℃ for 0.5-2 hours to obtain a reaction liquid R1;
(b) adding 3-ethoxy-4-methoxybenzaldehyde into a proper solvent, and reacting with strong weak nucleophilic base at-40-10 ℃ for 0.5-2 hours to obtain a reaction liquid R2;
(c) dripping R2 into R1, and reacting at-60-0 ℃ for 0.5-2 hours to obtain a reaction solution R3;
(d) adding boron trifluoride diethyl etherate into R3, and reacting at-80-0 ℃;
(e) quenching reaction, filtering, pulping and washing a filter cake by using dichloromethane, extracting an aqueous layer by using the filter cake, combining organic layers and concentrating;
(f) adding dichloromethane into the concentrated residue, washing with acid water, and separating;
(g) adjusting the pH value of a water layer to 10-14, extracting with dichloromethane, and concentrating an organic layer to obtain a crude product of the 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine.
According to the invention, 3-ethoxy-4-methoxybenzaldehyde is used as an initial raw material, and 1- (3-ethoxy-4-methoxy) phenyl-2-methylsulfonyl ethylamine is obtained through condensation, nucleophilic addition and trimethylsilyl removal, compared with the original grinding process, the method changes a feeding mode and a feeding ratio, and optimizes a purification method; compared with most of the currently reported or industrialized synthesis processes, the method improves the process level and operability, has good safety and higher product yield and purity, and is beneficial to large-scale industrial production.
Detailed Description
The present invention will be further described with reference to the following examples. The scope of the invention should not be construed as being limited to the particular embodiments discussed below. Without departing from the basic concept of the invention, simple deductions or equivalent replacements made by those skilled in the art according to the invention belong to the protection scope of the invention.
The present invention provides a process for the preparation of a compound of formula I, comprising the steps of:
(a) adding dimethyl sulfone into a proper solvent, and reacting with an organic lithium compound at the temperature of minus 40-10 ℃ for 0.5-2 hours to obtain a reaction liquid R1;
(b) adding 3-ethoxy-4-methoxybenzaldehyde into a proper solvent, and reacting with strong weak nucleophilic base at-40-10 ℃ for 0.5-2 hours to obtain a reaction liquid R2;
(c) dripping R2 into R1, and reacting at-60-0 ℃ for 0.5-2 hours to obtain a reaction solution R3;
(d) adding boron trifluoride diethyl etherate into R3, and reacting at-80-0 ℃;
(e) quenching reaction, filtering, pulping and washing a filter cake by using dichloromethane, extracting an aqueous layer by using the filter cake, combining organic layers and concentrating;
(f) adding dichloromethane into the concentrated residue, washing with acid water, and separating;
(g) adjusting the pH value of a water layer to 10-14, extracting with dichloromethane, and concentrating an organic layer to obtain a crude product of the 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine.
In some embodiments, step (a) is carried out at-20 to 0 ℃ for 1 hour.
In some embodiments, step (b) is carried out at-10 to 0 ℃ for 1 hour.
In some embodiments, step (c) is carried out at-40 to-30 ℃ for 1 hour.
In some embodiments, step (d) is reacted at-60 to-50 ℃.
In some embodiments, a suitable solvent is tetrahydrofuran.
In some embodiments, the organolithium compound is n-butyllithium.
In some embodiments, the strong, weakly nucleophilic base is sodium or potassium hexamethyldisilylamide.
In some embodiments, the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to dimethyl sulfone is from 1:3.6 to 4.5.
In some embodiments, the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to organolithium compound is 1:2 to 3.
In some embodiments, the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to strong, weakly nucleophilic base is 1:1 to 1.2.
In some embodiments, the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to boron trifluoride etherate is 1: 5.
In some embodiments, the crude 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine is recrystallized from toluene.
In some embodiments, the mass to volume ratio of crude 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine to toluene is 1: 4.
Example 1
1) To a 3L dry three-necked flask, Me was added in sequence2SO2 141 g (1.5 mol), THF (833 mL), stirring, nitrogen substitution three times and protection; cooling to-20 ℃, dropwise adding 500 mL (1.25 mol) of n-butyl lithium n-hexane solution, and controlling the temperature to be within-20-0 ℃. After the dropwise addition is finished, continuously controlling the temperature to be-20-0 ℃ and reacting for 0.5 h to prepare lithium salt R1 of dimethyl sulfone;
2) simultaneously with the above operation, 75 g (0.416 mol) of 3-ethoxy-4-methoxybenzaldehyde and THF (333 mL) were sequentially added to another 1L dry three-necked flask, and stirring was started, and nitrogen gas was replaced three times and protected; cooling to-10 ℃, dropwise adding 500 mL (0.5 mol) of tetrahydrofuran solution of lithium hexamethyldisilazide to control the internal temperature to be-10-0 ℃, and after dropwise adding, continuously controlling the temperature to be-10-0 ℃ to react for 1 h to prepare imine lithium salt R2;
3) cooling R1 to-30 to-40 ℃, dripping R2 into R1, controlling the internal temperature to-30 to-40 ℃, and stirring for 1 h under the same temperature condition after dripping;
4) cooling to-60 to-50 ℃, dropwise adding 293 g (2.08 mol) of boron trifluoride ether into the reaction solution, and controlling the internal temperature to-60 to-50 ℃. After the dropwise addition is finished, naturally heating to 0 ℃;
5) the reaction solution was quenched by adding potassium carbonate 91 g (0.66 mol) in 555 mL of aqueous solution, and the temperature was controlled to not exceed 15 ℃. After addition was complete, filtration was carried out, the filtrate was partitioned, the filter cake was washed twice with 500 mL of DCM and the aqueous phase was extracted with it. Combining the organic phases, and concentrating under pressure to dryness;
6) adding 300 mL of DCM and 330 mL of 4N HCl, stirring at 30 ℃ for 0.5 h, separating, extracting an organic layer once with 150 mL of 4N HCl, combining aqueous phases, and extracting and washing with 300 mL of DCM. Adding 4N NaOH into the water layer to adjust the pH value to 12-14, extracting 400mL of DCM twice, and concentrating to obtain 112.5 g of a crude product, wherein the yield is 99.1%, and the purity is 93.2%;
7) adding 112.5 g of the crude product and 450 mL of toluene into a 1L three-necked bottle, heating to reflux and dissolve, cooling to room temperature to precipitate a solid, carrying out ice bath crystallization for 2 h, and carrying out suction filtration to obtain 103.3 g of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine; the total yield is 91.0%; the purity is 98.9%.
Example 2
1) To a 5L dry three-necked flask, Me was added in sequence2SO2 352 g (3.74 mol), THF (1665 mL), stirring, nitrogen exchange three times and protection; cooling to-20 ℃, dropwise adding 1L (2.5 mol) of n-butyl lithium n-hexane solution, and controlling the temperature to be within-20-0 ℃. After the dropwise addition is finished, continuously controlling the temperature to be-20-0 ℃ and reacting for 1 h to prepare lithium salt R1 of dimethyl sulfone;
2) simultaneously with the above operation, another 2L dry three-necked flask was charged with 150 g (0.83 mol) of 3-ethoxy-4-methoxybenzaldehyde and THF (666 mL) in this order, stirred, and purged with nitrogen three times and protected; cooling to-10 ℃, dropwise adding 1L (1.0 mol) of tetrahydrofuran solution of lithium hexamethyldisilazide to control the internal temperature to be-10-0 ℃, and after dropwise adding, continuously controlling the temperature to be-10-0 ℃ to react for 1 h to prepare imine lithium salt R2;
3) cooling R1 to-30 to-40 ℃, dripping R2 into R1, controlling the internal temperature to-30 to-40 ℃, and stirring for 1 h under the same temperature condition after dripping;
4) cooling to-30 to-20 ℃, dropwise adding 589 g (4.15 mol) of boron trifluoride ether into the reaction solution, and controlling the internal temperature to-60 to-50 ℃. After the dropwise addition is finished, naturally heating to 0 ℃;
5) the reaction solution was quenched by adding 183 g (1.33 mol) of potassium carbonate to 1.11L of an aqueous solution, and the temperature was controlled to 15 ℃ or less. After the addition was complete, filtration was carried out, the filtrate was separated, and the filter cake was washed twice with DCM 1L by beating and the aqueous phase was extracted with it. Combining the organic phases, and concentrating under pressure to dryness;
6) 600 mL of DCM and 660 mL of 4N HCl are added, stirring is carried out at 30 ℃ for 0.5 h, liquid separation is carried out, an organic layer is extracted once by 300 mL of 4N HCl, water phases are combined, and 600 mL of DCM is washed by extraction. Adding 4N NaOH into the water layer to adjust the pH value to 12-14, extracting 800mL of DCM twice, and concentrating to obtain 234.4 g of crude product, wherein the yield is 103.3%, and the purity is 91.5%;
7) adding 234.4 g of crude product and 900 mL of toluene into a 1L three-necked bottle, heating to reflux and dissolve, cooling to room temperature to precipitate a solid, carrying out ice bath crystallization for 2 h, and carrying out suction filtration to obtain 207.7g of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine with a total yield of 91.5%; the purity is 98.8%.
Example 3
1) To a 5L dry three-necked flask, Me was added in sequence2SO2 282 g (3 mol), THF (1665 mL), with stirring, nitrogen replaced three times and protected; cooling to-20 ℃, dropwise adding 664 mL (1.66 mol) of n-butyl lithium n-hexane solution, and controlling the temperature to be within-20-0 ℃. After the dropwise addition is finished, continuously controlling the temperature to be-20-0 ℃ and reacting for 1 h to prepare lithium salt R1 of dimethyl sulfone;
2) simultaneously with the above operation, another 2L dry three-necked flask was charged with 150 g (0.83 mol) of 3-ethoxy-4-methoxybenzaldehyde and THF (666 mL) in this order, stirred, and purged with nitrogen three times and protected; cooling to-10 ℃, dropwise adding 1L (1.0 mol) of tetrahydrofuran solution of lithium hexamethyldisilazide to control the internal temperature to be-10-0 ℃, and after dropwise adding, continuously controlling the temperature to be-10-0 ℃ to react for 1 h to prepare imine lithium salt R2;
3) cooling R1 to-30 to-40 ℃, dripping R2 into R1, controlling the internal temperature to-30 to-40 ℃, and stirring for 1 h under the same temperature condition after dripping;
4) cooling to-30 to-20 ℃, dropwise adding 589 g (4.15 mol) of boron trifluoride ether into the reaction solution, and controlling the internal temperature to-60 to-50 ℃. After the dropwise addition is finished, naturally heating to 0 ℃;
5) the reaction solution was quenched by adding 183 g (1.33 mol) of potassium carbonate to 1.11L of an aqueous solution, and the temperature was controlled to 15 ℃ or less. After the addition was complete, filtration was carried out, the filtrate was separated, and the filter cake was washed twice with DCM 1L by beating and the aqueous phase was extracted with it. Mixing organic phases, and concentrating under pressure to dryness;
6) 600 mL of DCM and 660 mL of 4N HCl are added, stirring is carried out at 30 ℃ for 0.5 h, liquid separation is carried out, an organic layer is extracted once by 300 mL of 4N HCl, water phases are combined, and 600 mL of DCM is washed by extraction. Adding 4N NaOH into the water layer to adjust the pH value to 12-14, extracting 800mL of DCM twice, and concentrating to obtain 224.7 g of a crude product, wherein the yield is 99.0%, and the purity is 92.6%;
7) adding 224.7 g of the crude product and 900 mL of toluene into a 1L three-necked bottle, heating to reflux and dissolve, cooling to room temperature to precipitate a solid, carrying out ice bath crystallization for 2 h, and carrying out suction filtration to obtain 204.4 g of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine with the total yield of 90.0%; the purity is 99.0%.
Example 4
1) To a 5L dry three-necked flask, Me was added in sequence2SO2 282 g (3 mol), THF (1665 mL), with stirring, replaced three times with nitrogen and protected; cooling to-20 ℃, dropwise adding 664 mL (1.66 mol) of n-butyl lithium n-hexane solution, and controlling the temperature to be within-20-0 ℃. After the dropwise addition is finished, continuously controlling the temperature to be-20-0 ℃ and reacting for 2 hours to prepare lithium salt R1 of dimethyl sulfone;
2) simultaneously with the above operation, another 2L dry three-necked flask was charged with 150 g (0.83 mol) of 3-ethoxy-4-methoxybenzaldehyde and THF (666 mL) in this order, stirred, and purged with nitrogen three times and protected; cooling to-10 ℃, dropwise adding 830 mL (0.83 mol) of tetrahydrofuran solution of lithium hexamethyldisilazide to control the internal temperature to be-10-0 ℃, and after dropwise adding, continuously controlling the temperature to be-10-0 ℃ to react for 1 h to prepare imine lithium salt R2;
3) cooling R1 to-30 to-40 ℃, dripping R2 into R1, controlling the internal temperature to-30 to-40 ℃, and stirring for 1 h under the same temperature condition after dripping;
4) cooling to-30 to-20 ℃, dropwise adding 589 g (4.15 mol) of boron trifluoride ether into the reaction solution, and controlling the internal temperature to-60 to-50 ℃. After the dropwise addition is finished, naturally heating to 0 ℃;
5) the reaction solution was quenched by adding 183 g (1.33 mol) of potassium carbonate to 1.11L of an aqueous solution, and the temperature was controlled to 15 ℃ or less. After the addition was complete, filtration was carried out, the filtrate was separated, and the filter cake was washed twice with DCM 1L by beating and the aqueous phase was extracted with it. Combining the organic phases, and concentrating under pressure to dryness;
6) 600 mL of DCM and 660 mL of 4N HCl are added, stirring is carried out at 30 ℃ for 0.5 h, liquid separation is carried out, an organic layer is extracted once by 300 mL of 4N HCl, water phases are combined, and 600 mL of DCM is washed by extraction. Adding 4N NaOH into the water layer to adjust the pH value to 12-14, extracting 800mL of DCM twice, and concentrating to obtain 226.3 g of a crude product, wherein the yield is 99.7%, and the purity is 92.4%;
7) adding 226.3 g of the crude product and 900 mL of toluene into a 1L three-necked bottle, heating to reflux and dissolve, cooling to room temperature to precipitate a solid, carrying out ice bath crystallization for 2 h, and carrying out suction filtration to obtain 207.3g of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine with the total yield of 91.3%; the purity is 98.8%.
Claims (8)
1. A preparation method of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine, an apremilast intermediate shown in formula (I), is characterized by comprising the following steps:
(a) adding dimethyl sulfone into a proper solvent, and reacting with an organic lithium compound at the temperature of-20-0 ℃ for 1 hour to obtain a reaction liquid R1;
(b) adding 3-ethoxy-4-methoxybenzaldehyde into a proper solvent, and reacting with strong weak nucleophilic base at-10-0 ℃ for 1 hour to obtain a reaction solution R2;
(c) dripping R2 into R1, and reacting at-40 to-30 ℃ for 1 hour to obtain a reaction solution R3;
(d) adding boron trifluoride ether into R3, and reacting at-60 to-50 ℃;
(e) quenching reaction, filtering, pulping and washing a filter cake by using dichloromethane, extracting an aqueous layer by using the filter cake, combining organic layers and concentrating;
(f) adding dichloromethane into the concentrated residue, washing with acid water, and separating;
(g) adjusting the pH value of a water layer to 10-14, extracting with dichloromethane, and concentrating an organic layer to obtain a crude product of 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine;
wherein the suitable solvent is tetrahydrofuran, the organolithium compound is n-butyllithium, and the strong, weakly nucleophilic base is sodium or potassium hexamethyldisilylamide.
2. The method of claim 1, wherein the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to dimethyl sulfone is 1:3.6 to 4.5.
3. The method according to claim 2, wherein the molar ratio of the 3-ethoxy-4-methoxybenzaldehyde to the organolithium compound in step (a) is 1:2 to 3.
4. The method of claim 3, wherein the molar ratio of the 3-ethoxy-4-methoxybenzaldehyde to the strong, weakly nucleophilic base in step (b) is 1:1 to 1.2.
5. The process according to claim 4, wherein the molar ratio of 3-ethoxy-4-methoxybenzaldehyde to boron trifluoride etherate in step (d) is 1: 5.
6. The process of any one of claims 1 to 5, further comprising the step of refining the crude product of step (g).
7. The process of claim 6, further comprising the step of refining the crude product of step (g) in toluene.
8. The method of claim 7, wherein the mass to volume ratio of crude 1- (3-ethoxy-4-methoxyphenyl) -2- (methylsulfonyl) ethylamine to toluene is 1: 4.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2000025777A1 (en) * | 1998-10-30 | 2000-05-11 | Celgene Corporation | SUBSTITUTED PHENETHYLSULFONES AND METHOD OF REDUCING TNFαLEVELS |
| WO2012083153A1 (en) * | 2010-12-16 | 2012-06-21 | Nektar Therapeutics | Oligomer-containing apremilast moiety compounds |
| CN104803897A (en) * | 2015-04-23 | 2015-07-29 | 中山奕安泰医药科技有限公司 | Synthetic process of Apremilast intermediate |
| WO2015181249A1 (en) * | 2014-05-28 | 2015-12-03 | Lek Pharmaceuticals D.D. | PROCESSES FOR THE PREPARATION OF β-AMINOSULFONE COMPOUNDS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000025777A1 (en) * | 1998-10-30 | 2000-05-11 | Celgene Corporation | SUBSTITUTED PHENETHYLSULFONES AND METHOD OF REDUCING TNFαLEVELS |
| WO2012083153A1 (en) * | 2010-12-16 | 2012-06-21 | Nektar Therapeutics | Oligomer-containing apremilast moiety compounds |
| WO2015181249A1 (en) * | 2014-05-28 | 2015-12-03 | Lek Pharmaceuticals D.D. | PROCESSES FOR THE PREPARATION OF β-AMINOSULFONE COMPOUNDS |
| CN104803897A (en) * | 2015-04-23 | 2015-07-29 | 中山奕安泰医药科技有限公司 | Synthetic process of Apremilast intermediate |
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