CN104447445A - Preparation method for synthesizing apremilast intermediate - Google Patents
Preparation method for synthesizing apremilast intermediate Download PDFInfo
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Abstract
The invention relates to a preparation method for synthesizing an apremilast intermediate. The preparation method comprises the following steps of: carrying out condensation reaction on 3-ethoxyl-4-methoxyl-benzoate and dimethyl sulfone under an alkaline condition to generate 2-(3-ethoxy-4-methoxyphenyl)-1-methylsulfonyl acetone; reacting the compound II and chiral amine in the presence of an acidic catalyst to obtain 1-N-substituted amino-1-(3-ethoxyl-4-methoxyl) phenyl-2-methylsulfonyl ethylene (III), and directly hydrogenating the obtained compound III in the presence of a hydrogenation catalyst without separating the compound III to obtain a product (S)-1-(3-ethoxyl-4-methoxyl) phenyl-2-methanesulfonyl ethylamine (I), namely the apremilast intermediate, wherein the apremilast intermediate can be further prepared into N-acetyl L-leucinate. The invention also provides a preparation method of apremilast. The preparation method disclosed by the invention has the advantages of simple process flow, safety, environmental friendliness and low cost and is favorable to clean industrialized production.
Description
Technical field
The present invention relates to a kind of simple and convenient process for preparing of synthesis Apremilast intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine, belong to medicine bioengineering chemical field.
Background technology
(S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I) is the key intermediate preparing Apremilast.Apremilast (Apremilast) is the oral pharmaceutical for the treatment of reactivity psoriatic arthritis; chemical name is (S)-2-[1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-acetylaminoisoindoline-1; 3-diketone, CAS 608141-41-9.This medicine in March, 2014 with trade(brand)name Otezla (Apremilast) obtain FDA approval, be FDA approval first be also unique one for psoriasis in plaques treatment oral, selectivity phosphodiesterase 4 (PDE4) inhibitor.
US Patent No. 6962940 first reported the synthetic method of Apremilast, and obtained by two key intermediate condensations, synthetic route is shown in reaction scheme 1:
The reaction scheme 1 of above-mentioned US6962940 adopts the method for first synthesizing racemic product and splitting, and result in the waste of a large amount of (R)-enantiomorph, the intermediate utilization ratio of synthesis only has 50%, and total recovery only has 13%.Meanwhile, owing to using the raw material that the operational requirements such as n-Butyl Lithium are high, the production of large-scale is restricted.Racemic product splits again, also needs to use a large amount of resolving agent, causes cost to raise, and introduces a large amount of impurity for follow-up synthesis.
Celgene Corp. uses following route to synthesize key intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I) of Apremilast in US2013217918 and US2014081032:
Above-mentioned reaction scheme 2 adopts the method for chiral synthesize to prepare chiral intermediate, but the raw material 3-oxyethyl group-4-methoxy cyanophenyl used is expensive, uses butyllithium as alkali simultaneously, and large-scale production is restricted; Reaction process uses a large amount of solvents and soda acid, adds the discharge of " three wastes ", is unfavorable for environmental protection.
Reaction scheme 3 and reaction scheme 4 all with 3-oxyethyl group-4-methoxybenzaldehyde for raw material, adopt the method for chiral synthesize to obtain product.But use butyllithium as alkali, not easily industrial operation, and the optical purity that the method obtains product only have 80%, do not reach product requirement far away, still need to purify, and the subsequent product that is introduced as of resolving agent introduces new impurity, and add operation steps.
Chinese patent CN103864670A discloses the method for synthesis Apremilast, describes following reaction scheme:
Above-mentioned reaction scheme 5 employs dimethyl sulfone list lithium salts when addition reaction, and this single lithium salts is dimethyl sulfone and butyllithium prepares in aprotic solvent, inevitably uses the lithiumation thing that butyllithium etc. is active, not easy to operate.Meanwhile, use macromole highly selective Chiral Amine, decrease molecule utilization ratio, without industrial value.
Summary of the invention
For the deficiencies in the prior art; the invention provides a kind of preparation method synthesizing Apremilast intermediate, also namely: provide one to prepare the easy technique of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I).
The present invention also provides a kind of method utilizing (S)-1-of preparation (3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I) to prepare Apremilast further.
Technical scheme of the present invention is as follows:
The preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine shown in a kind of formula (I),
By making 3-oxyethyl group-4-methoxy-benzoic acid ester in solvent orange 2 A, under nitrogen protection and highly basic exist, carry out condensation reaction with dimethyl sulfone, generate the compound shown in formula II: 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone;
Described highly basic is one of solid sodium methylate, solid sodium ethanol, potassium tert.-butoxide, sodium hydride or combination;
Described 3-oxyethyl group-4-methoxybenzoic acid ester: highly basic: mol ratio=1:(1 ~ 3 of dimethyl sulfone): (1 ~ 10);
Described solvent orange 2 A is one of normal hexane, hexanaphthene, toluene, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyltetrahydrofuran or combination;
Gained formula II compound is in solvent B; carry out enamine in the presence of acidic with Chiral Amine and be obtained by reacting the compound shown in formula III: 1-N-substituted-amino-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III)
Described solvent B is acetic acid, methyl alcohol, ethanol, propyl alcohol, hexanaphthene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, one of toluene or haloalkane or combination; Described Chiral Amine is the aromatic amine containing chiral amino, the aliphatic amide containing chiral amino or chiral amino acid;
This compound (III), without separation directly hydrogenation under hydrogenation catalyst effect, obtains (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine of formula (I).
According to the present invention, optimum condition is following:
The setting-up point of described 3-oxyethyl group-4-methoxy-benzoic acid ester and dimethyl sulfone is 0-50 DEG C, and the reaction times is 2-12 hour; Preferred 15-35 DEG C further, the reaction times is 5-8 hour.
Described alkene amination reaction temperature is-30 DEG C to 85 DEG C, and preferably-5 DEG C-30 DEG C, the reaction times is 2-20 hour;
Described hydrogenation temperature is-40 DEG C to 120 DEG C, preferably-15 DEG C to 80 DEG C, most preferably-5 DEG C to 40 DEG C.
According to the present invention, preferred scheme is as follows:
A kind of preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine, comprises step as follows:
(1) under nitrogen protection, in solvent orange 2 A, highly basic is added; in keeping between warm 15-25 DEG C; drip dimethyl sulfone, be warming up to 30-35 DEG C, drip the solvent orange 2 A mixing solutions of 3-oxyethyl group-4-methoxy-benzoic acid ester; carry out condensation reaction; react complete, with the neutralization of ammonium chloride saturated solution, extraction; organic phase recycling design, obtained 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II).
(2) under nitrogen protection, to in solvent B, add 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II), stir, in keeping between temperature 5 DEG C to 15 DEG C, add an acidic catalyst, or also can add appropriate dewatering agent, drip the mixing solutions of Chiral Amine and solvent B subsequently, described 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II): Chiral Amine mol ratio=1:2 to 1:1;
Then 10 DEG C of insulation reaction 2-3 hour, obtain the mixed solution of N-(1-methyl isophthalic acid-phenyl) methyl isophthalic acid-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine;
(3) under nitrogen protection, in above-mentioned mixed solution, add methyl alcohol or ethanol, and add hydrogenation catalyst, nitrogen replacement 3 times, in keeping between temperature 0 DEG C to 5 DEG C, with hydrogen exchange, after hydrogen exchange, keep hydrogen pressure (reduction pressure) between 0-4.5MPa, subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C, hydrogen pressure strengthens 0.05-0.2MPa again, and insulation hydrogenation reaction, no longer drops to reaction terminating to hydrogen pressure;
After above-mentioned hydrogenation reaction terminates; cooling; nitrogen replacement; filter, gained solution is concentrated into dry, reclaim methyl alcohol or ethanol; residual residue is dissolved in water; dichloromethane extraction, combined dichloromethane phase, is concentrated into dry (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine shown in product formula (I).
According to the present invention, preferably, described starting raw material 3-oxyethyl group-4-methoxy-benzoic acid ester is 3-oxyethyl group-4-methoxybenzoic acid fatty ester or 3-oxyethyl group-4-methoxybenzoic acid aromatic ester; Wherein: described 3-oxyethyl group-4-methoxybenzoic acid fatty ester, 3-oxyethyl group-4-methoxyl methyl benzoate or 3-oxyethyl group-4-methoxy ethylbenzoate is preferably; Described 3-oxyethyl group-4-methoxybenzoic acid aromatic ester is preferably 3-oxyethyl group-4-methoxybenzoic acid benzyl ester.
According to the present invention, preferably, described solvent orange 2 A is hexanaphthene, normal hexane, dimethyl sulfoxide (DMSO) and tetrahydrofuran (THF), and preferred solvent orange 2 A is one or its mixed solvent of hexanaphthene, normal hexane and dimethyl sulfoxide (DMSO).
According to the present invention, preferably, the mol ratio=1:1.5:6 to 1:1:2 of described 3-oxyethyl group-4-methoxybenzoic acid ester, highly basic, dimethyl sulfone.
According to the present invention, preferably, described an acidic catalyst is tosic acid; Or an acidic catalyst adds fashionable also with addition of appropriate dewatering agent, and dewatering agent is selected from titanium tetrachloride or 4A molecular sieve.
According to the present invention, preferably, described Chiral Amine is chiral benzhydryl base ethamine, chirality o-hydroxy ethamine, chirality naphthalene ethylamine, the adjacent hydroxyl naphthalene ethylamine of chirality, chirality phenylethylamine or chiral alpha-aminopropanol.
Preferred further, described Chiral Amine is selected from: one of L-α aminopropanol, S-1-naphthalene ethylamine, S-1-phenylethylamine.
According to the present invention, preferably, described formula II compound: Chiral Amine mol ratio=1:(1.2-1.6).
According to the present invention, preferably, described hydrogenation catalyst is Pd/C catalyzer or Raney's nickel, wherein most preferably carries the Pd/C catalyzer of Pd weight 5-10%.
According to the present invention, preferably, in described hydrogenation reaction, hydrogen pressure controls within the scope of 0-3MPa, more preferably hydrogenation under 0.05-0.5MPa low pressure.Hydrogenation reaction time 1-10 hour, further preferred 1-4 hour.
In order to energy long-time storage; ensure that chiral intermediate racemization does not occur; the present invention is also preferred by formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine; react salify with N-acetamido L-Leu, be prepared into (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine N-ethanoyl-L-Leu salt.Structure is as shown in the formula shown in (IV):
The present invention also provides a kind of preparation method of Apremilast; comprise preparation process (1)-(3) of above-mentioned formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine; it is characterized in that, also continue following steps:
(4) by making formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine and the condensation of 3-kharophen Tetra hydro Phthalic anhydride prepare Apremilast; Or:
Make formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine and 3-kharophen Tetra hydro Phthalic anhydride and N-acetamido L-Leu react salify, then prepare Apremilast with the condensation of 3-kharophen Tetra hydro Phthalic anhydride.
In the preparation method of above-mentioned Apremilast, preferably, formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine and 3-kharophen Tetra hydro Phthalic anhydride carry out condensation reaction under catalyzer (perchloric acid) exists, 20-40 minute is reacted, then temperature rising reflux reaction 1-2.5 hour between 75-80 DEG C; Reaction terminates rear recycling design II, adds ethyl acetate and water, layering, and organic phase is dry, concentrated, and resistates recrystallisation from isopropanol prepares Apremilast.
In method of the present invention, the compound ii that starting raw material 3-oxyethyl group-4-methoxy-benzoic acid ester and dimethyl sulfone condensation obtain in a suitable solvent, with Chiral Amine in the presence of acidic enamine be obtained by reacting compound III: 1-N-substituted-amino-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III), compound III without separation directly under catalyst action hydrogenation obtain formula (I) intermediate: (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I); Then for the preparation of Apremilast.The reaction related in the present invention, as shown in following reaction scheme 6:
The method utilizes stable 3-oxyethyl group-4-methoxy-benzoic acid ester as raw material, adopt conventional basic catalyst, dimethyl sulfone obtains intermediate compound (II) in alkaline bar condensation one step, compound (II) and Chiral Amine in the presence of acidic enamine are obtained by reacting 1-N-substituted-amino-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III), compound III is without separation directly hydrogenation under catalyst action, (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I) is obtained by the slow cis hydrogenation selectivity under catalysis, Apremilast is prepared in chemical compounds I and the condensation of 3-kharophen Tetra hydro Phthalic anhydride, compound (I) also can react after salify obtains compound (IV) with N-acetamido L-Leu, then prepares Apremilast with the condensation of 3-kharophen Tetra hydro Phthalic anhydride.After chiral intermediate salify, not easily there is racemization, be convenient to store, the optical purity after chiral intermediate long-time storage can be ensured.
Technical characterstic of the present invention and excellent results:
1, feedstock property of the present invention is stablized inexpensive, reacts simple and easy to control." one kettle way " carries out enamine, enamine reduction and takes off N-aryl-response, and decrease using and being separated of solvent, technical process is short, and avoids the reaction conditions of the harshnesses such as very low temperature, improves process safety, is conducive to operation; Decrease discharge of wastewater, economic environmental protection simultaneously.
2, intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine (I) related impurities that obtains of the inventive method is few; product purity is high; HPLC purity can reach more than 99.5%; optical purity can reach more than 98.5%, and utilizing this intermediate to synthesize Apremilast total recovery can up to more than 65%.
3, concise in technology of the present invention, cost is low, route safety and environmental protection, is beneficial to clean suitability for industrialized production, significant to the synthesis of Apremilast medicine.
Embodiment
Condensation reaction, enamine are reacted and the process monitoring of reduction reaction utilizes HPLC to detect; the finished product (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine utilizes chiral column HPLC to detect purity (area ratio %), and calculated yield and e.e. value.
Describe the present invention in detail below in conjunction with embodiment, but the present invention is not only confined to this.
The preparation of embodiment 1:1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II)
Under nitrogen protection; 200 grams of normal hexanes are added successively in 1000 milliliters of glass flask of drying; 24 grams (0.6 mole) 60% solid hydride sodium; cooling; in keeping between temperature 15 DEG C to 25 DEG C; drip 188 grams of (2 moles) dimethyl sulfone, within about 2 hours, dropwise, be after this warming up to 35 DEG C insulation reaction 1-2 hour (priming reactions).Then in keeping between temperature 30 DEG C to 35 DEG C, drip the mixing solutions of 126.6 grams of 3-oxyethyl group-4-methoxyl methyl benzoates (0.6 mole) and 200 grams of normal hexanes, within about 2 hours, drip and finish, drip and finish 35 DEG C of reactions 4 hours.Be cooled to 20 DEG C; drip 110 grams of saturated aqueous ammonium chlorides; static layering; water layer 100 grams of extraction into ethyl acetate 3 times, organic phase merges, 30 grams of anhydrous sodium sulfate dryings 4 hours; filter; filtrate recycling design obtains off-white color solid 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II) 156.4 gram, yield 95%, HPLC purity 98.3%.
The preparation of embodiment 2:1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II)
Under nitrogen protection, in 1000 milliliters of glass flask of drying, add 200g dimethyl sulfoxide (DMSO) successively, 200 grams of dimethyl sulfone; 89.6 grams of (0.8 mole) potassium tert.-butoxides; cooling, keep in temperature 10 DEG C to 20 DEG C between 2 hours, be after this warming up to 30 DEG C of insulation reaction 1 to 2 hour.Then in keeping between temperature 33 DEG C to 35 DEG C, add 126.6 grams of 3-oxyethyl group-4-methoxyl methyl benzoates (0.6 mole) in batches, finish 35 DEG C of reactions 4 hours.Be cooled to 20 DEG C; drip 118 grams of saturated aqueous ammonium chlorides; static layering, water layer 100 grams of extraction into ethyl acetate 3 times, organic phase merges; 30 grams of anhydrous sodium sulfate dryings 4 hours; filter, filtrate recycling design, obtains off-white color solid 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II) 147.7 gram; yield 89.7%, HPLC purity 98.9%.
The preparation of embodiment 3:1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II)
Under nitrogen protection; 180 grams of hexanaphthenes are added successively in 1000 milliliters of glass flask of drying; 36 grams (0.9 mole) 60% solid hydride sodium; cooling; in keeping between temperature 20 DEG C to 25 DEG C; drip 141 grams of (1.5 moles) dimethyl sulfone, within about 2 hours, dropwise, be after this warming up to 35 DEG C of insulation reaction 1 to 2 hour.Then warm 34-35 DEG C in keeping, drips the mixing solutions of 134.4 grams of 3-oxyethyl group-4-methoxy ethylbenzoate (0.6 mole) and 200 grams of hexanaphthenes, within about 2 hours, drips and finishes, and drips and finishes 35 DEG C of reactions 4 hours.Be cooled to 20 DEG C; drip 165 grams of saturated aqueous ammonium chlorides; static layering, water layer 150 grams of extraction into ethyl acetate 3 times, organic phase merges; 30 grams of anhydrous sodium sulfate dryings 4 hours; filter, filtrate recycling design, obtains micro-yellow solid 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II) 156.4 gram; yield 84.2%, HPLC purity 96.4%.
Embodiment 4:(S) preparation of-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; 400 grams of hexanaphthenes are added successively in 1000 milliliters of glass flask of drying; 137 grams of (0.5 mole) 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyls ethyl ketone (II); cool after stirring; in keeping between temperature 5 DEG C to 15 DEG C; add 6.0 grams of tosic acid (0.037 mole) and 1.9 grams of titanium tetrachlorides (0.01 mole), drip the solution of 84 grams of S-1-phenylethylamines (0.7 mole) and 200 grams of hexanaphthenes subsequently, within about 2 hours, dropwise.After this 10 DEG C of insulation reaction 2 to 3 hours.The mixing solutions obtained, sampling detects, and it is 99.7% that HPLC shows feed stock conversion, and intermediate N (1-methyl isophthalic acid-phenyl) methyl isophthalic acid-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine, yield is 98%.
Under nitrogen protection; 100 grams of methyl alcohol and 5 grams of 10%Pd/C solids are added in above-mentioned mixed solution; cooling; after nitrogen replacement 3 times; in keeping between temperature 0 DEG C to 5 DEG C; after hydrogen exchange; keep hydrogen pressure between 0.05MPa-0.1MPa; subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C; hydrogen pressure is increased to 0.1-0.3MPa, insulation reaction 1 hour, continue to hydrogen pressure do not decline (sampling; chirality HPLC is adopted to detect, chirality optical purity > 99%).
After insulation terminates; cooling, nitrogen replacement, filters; the mixed solution obtained is concentrated into dry; residual residue adds 200 grams of water dissolution, with 100 grams of dichloromethane extractions 3 times, and combined dichloromethane phase; be concentrated into and dryly obtain (S)-1-(3-oxyethyl group-4-methoxyl group) 119.6 grams, phenyl-2-methylsulfonyl ethamine; yield 86.34%, purity 99.4%, chirality optical purity 98.7%.
Products therefrom (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine is compound as white solid: fusing point 107.6-108.5 DEG C.
Chirality HPLC: chirality test column chiralpak AD, 250mm × 4.6mm, column oven temperature 25 DEG C, moving phase heptane: Virahol: diethylamine is 55:45:0.1, flow velocity 1ml/min, determined wavelength 240nm, 17.6min (S-type isomer) 99.35%, 24.4min (R-type isomer) 0.65%.
HPLC:Aquity UPLC C18,2.1mm × 150mm, moving phase acetonitrile: 0.1% phosphate aqueous solution by 10:90 to 90:10, flow: 0.85ml/min, determined wavelength 240nm, column oven temperature 35 DEG C, area normalization method 99.4%.
1hNMR composes (CDCl
3, 400MHz): 1.44 (t, J=7.0HZ, 3H), 1.87 (bs, 2H), 2.88 (s, 3H), 3.20 (dd, J
1,2=3.0Hz, J
1,3=14.0Hz, 1H), 3.30 (dd, J
1,2=9.5Hz, J
1,3=14.0Hz, 1H), 3.83 (s, 3H), 4.08 (q, J7.0Hz, 2H), 4.55 (dd, J
1,2=3.0Hz, J
1,3=9.5Hz, 1H), 6.90 (m, 3H).
Embodiment 5:(S) preparation of-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; 300 grams of methyl alcohol are added successively in 1000 milliliters of glass flask of drying; 137 grams of (0.5 mole) 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyls ethyl ketone (II); cool after stirring; add 6.0 grams of tosic acid (0.037 mole) and 4A molecular sieve; in keeping between temperature 5 DEG C to 15 DEG C; drip the solution of 52.5 grams of L-α aminopropanols (0.7 mole) and 60 grams of methyl alcohol subsequently, within about 2 hours, dropwise.After this 10 DEG C of insulation reaction 2 to 3 hours.The mixing solutions obtained, sampling detects, and it is 97.1% that HPLC shows feed stock conversion, and intermediate N (1-methyl isophthalic acid-methylol) methyl isophthalic acid-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine yield is 96.7%.
Under nitrogen protection; the mixing liquid of 50 grams of methyl alcohol and 5 grams of 10%Pd/C solids is added in above-mentioned mixed solution; cooling; after nitrogen replacement 3 times; in keeping between negative 5 DEG C to 5 DEG C of temperature; after hydrogen exchange; keep hydrogen pressure between 0.05MPa-0.12MPa; subsequently temperature in the kettle is increased to 30 DEG C-35 DEG C; hydrogen pressure is increased to 0.2-0.38MPa, insulation reaction 3 hours, continue to hydrogen pressure do not decline (sampling; chirality HPLC is adopted to detect, chirality optical purity > 99%).After insulation terminates; cooling, nitrogen replacement, filters; the mixed solution obtained is concentrated into dry; residual residue adds 200 grams of water dissolution, with 100 grams of dichloromethane extractions 3 times, and combined dichloromethane phase; be concentrated into and dryly obtain (S)-1-(3-oxyethyl group-4-methoxyl group) 126 grams, phenyl-2-methylsulfonyl ethamine; yield 90.9%, purity 99.5%, chirality optical purity 99.4%.Embodiment 6:(S) preparation of-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methyl sulphonyl ethamine (I)
Under nitrogen protection; 300 grams of ethanol are added successively in 1000 milliliters of glass flask of drying; 137 grams of (0.5 mole) 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyls ethyl ketone (II); cool after stirring; add 6.0 grams of tosic acid (0.037 mole); in keeping between temperature 5 DEG C to 15 DEG C, drip the solution of 150 grams of S-1-naphthalene ethylamines (0.7 mole) and 100 grams of methyl alcohol subsequently, within about 3 hours, dropwise.After this 10 DEG C of insulation reaction 2 to 3 hours.The mixing solutions obtained, sampling detects, and it is 99.5% that HPLC shows feed stock conversion, and intermediate N (1-methyl isophthalic acid-naphthyl) methyl isophthalic acid-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine yield is 97.7%.
Under nitrogen protection; the mixing liquid of 50 grams of ethanol and 5 grams of 10%Pd/C solids is added, cooling, after nitrogen replacement 3 times in above-mentioned mixed solution; in keeping between temperature 5 DEG C to 15 DEG C; after hydrogen exchange, keep hydrogen pressure between 0.05MPa-0.09MPa, subsequently temperature in the kettle is increased to 30 DEG C-35 DEG C; hydrogen pressure is increased to 0.1-0.26MPa; insulation reaction 2.5 hours (sampling adopts chirality HPLC to detect, chirality optical purity > 99%).After insulation terminates; cooling, nitrogen replacement, filters; the mixed solution obtained is concentrated into dry; residual residue adds 200 grams of water dissolution, with 100 grams of dichloromethane extractions 3 times, and combined dichloromethane phase; be concentrated into and dryly obtain (S)-1-(3-oxyethyl group-4-methoxyl group) 128.8 grams, phenyl-2-methylsulfonyl ethamine; yield 93%, purity 99.1%, chirality optical purity 99.6%.
Embodiment 7:(S) preparation of-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine N-ethanoyl-L-Leu salt
Under nitrogen protection, to mechanical stirring is housed, (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl 110 grams, ethamine (0.4mol) is added in drying 1000 milliliters of glass flask of thermometer and prolong, N-ethanoyl leucine 69.3 grams (0.4mol) and methyl alcohol 500 grams, backflow is heated to 1 hour under stirring, then under whipped state, be cooled to envrionment temperature, and at room temperature stir 3 hours, filter, and use methanol wash filter cake, subsequently under vacuo dry cake to constant weight, obtain 176.3 grams of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine N-ethanoyl-L-Leu salt (optical purity 99.6%) yield 98.3%.
Chirality HPLC (ethanol: 20mMKH
2pO
4=1:99, PH=7.0, the ES-OVM chiral chromatographic column of Agilent company, 150mm × 4.6mm, flow velocity is 0.5ml/min, and determined wavelength is 240nm): 18.1min (S type isomer, 99.6%), 25.0min (R type isomer, 0.4%)
The preparation of embodiment 8:S-2-[1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-aminoisoindoline-1,3-diketone (Apremilast)
Under nitrogen protection, (S)-1-(3-oxyethyl group-4-methoxyl group) 60.0 grams (0.22 mole, phenyl-2-methylsulfonyl ethamine is added successively in 1000 milliliters of glass flask of drying, 99.4%e.e.), 3-kharophen Tetra hydro Phthalic anhydride (49.0 grams, 0.23mol) with 500 grams, Glacial acetic acid, after stirring, 3 grams, perchloric acid is dripped in 30 minutes, react 30 minutes between temperature 65 DEG C to 85 DEG C in keeping, temperature rising reflux 2 hours subsequently, remove recovery Glacial acetic acid subsequently under reduced pressure, then leftover materials are cooled to room temperature, add 200 grams of saturated aqueous common salts and 300 grams of acetic acid ethyl dissolutions respectively, stir layering, divide and get organic phase, evaporated under reduced pressure, residue obtains 82.8 grams of solids (yield 80%) after recrystallisation from isopropanol, for Apremilast (S-2-[1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonylethyl]-4-aminoisoindoline-1, 3-diketone), optical purity 99.1%, purity 99.5%.
Claims (10)
1. a preparation method for (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine shown in formula (I),
By making 3-oxyethyl group-4-methoxy-benzoic acid ester in solvent orange 2 A, under nitrogen protection and highly basic exist, carry out condensation reaction with dimethyl sulfone, generate the compound shown in formula II: 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone;
Described highly basic is one of solid sodium methylate, solid sodium ethanol, potassium tert.-butoxide, sodium hydride or combination;
Described 3-oxyethyl group-4-methoxybenzoic acid ester: highly basic: mol ratio=1:(1 ~ 3 of dimethyl sulfone): (1 ~ 10);
Described solvent orange 2 A is one of normal hexane, hexanaphthene, toluene, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), 2-methyltetrahydrofuran or combination;
Gained formula II compound is in solvent B; carry out enamine in the presence of acidic with Chiral Amine and be obtained by reacting the compound shown in formula III: 1-N-substituted-amino-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene (III)
Described solvent B is acetic acid, methyl alcohol, ethanol, propyl alcohol, hexanaphthene, tetrahydrofuran (THF), 2-methyltetrahydrofuran, methyl tert-butyl ether, one of toluene or haloalkane or combination; Described Chiral Amine is the aromatic amine containing chiral amino, the aliphatic amide containing chiral amino or chiral amino acid;
This compound (III), without separation directly hydrogenation under hydrogenation catalyst effect, obtains (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine of formula (I).
2. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, comprises step as follows:
(1) under nitrogen protection, in solvent orange 2 A, highly basic is added, in keeping between warm 15-25 DEG C, drip dimethyl sulfone, be warming up to 30-35 DEG C, drip the solvent orange 2 A mixing solutions of 3-oxyethyl group-4-methoxy-benzoic acid ester, carry out condensation reaction, react complete, with the neutralization of ammonium chloride saturated solution, extraction, organic phase recycling design, obtained 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II);
(2) under nitrogen protection, to in solvent B, add 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II), stir, in keeping between temperature 5 DEG C to 15 DEG C, add an acidic catalyst, or also can add appropriate dewatering agent, drip the mixing solutions of Chiral Amine and solvent B subsequently, described 1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethyl ketone (II): Chiral Amine mol ratio=1:2 to 1:1;
Then 10 DEG C of insulation reaction 2-3 hour, obtain the mixed solution of N-(1-methyl isophthalic acid-phenyl) methyl isophthalic acid-(3-oxyethyl group-4-methoxyl group) phenyl-2-methanesulfonyl-ethene amine;
(3) under nitrogen protection, in above-mentioned mixed solution, add methyl alcohol or ethanol, and add hydrogenation catalyst, nitrogen replacement 3 times, in keeping between temperature 0 DEG C to 5 DEG C, with hydrogen exchange, after hydrogen exchange, keep hydrogen pressure (reduction pressure) between 0-4.5MPa, subsequently temperature in the kettle is increased to 25 DEG C-35 DEG C, hydrogen pressure strengthens 0.05-0.2MPa again, and insulation hydrogenation reaction, no longer drops to reaction terminating to hydrogen pressure;
After above-mentioned hydrogenation reaction terminates; cooling; nitrogen replacement; filter, gained solution is concentrated into dry, reclaim methyl alcohol or ethanol; residual residue is dissolved in water; dichloromethane extraction, combined dichloromethane phase, is concentrated into dry (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine shown in product formula (I).
3. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that described starting raw material 3-oxyethyl group-4-methoxy-benzoic acid ester is 3-oxyethyl group-4-methoxybenzoic acid fatty ester or 3-oxyethyl group-4-methoxybenzoic acid aromatic ester.
4. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that the mol ratio=1:1.5:6 to 1:1:2 of described 3-oxyethyl group-4-methoxybenzoic acid ester, highly basic, dimethyl sulfone.
5. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that described an acidic catalyst is tosic acid.
6. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that described Chiral Amine is chiral benzhydryl base ethamine, chirality o-hydroxy ethamine, chirality naphthalene ethylamine, the adjacent hydroxyl naphthalene ethylamine of chirality, chirality phenylethylamine or chiral alpha-aminopropanol.
7. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that described formula II compound: Chiral Amine mol ratio=1:(1.2-1.6).
8. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1, is characterized in that described hydrogenation catalyst is Pd/C catalyzer or Raney's nickel; Preferably carry the Pd/C catalyzer of Pd 5-10% weight ratio.
9. the preparation method of (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine as claimed in claim 1; it is characterized in that formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine; react salify with N-acetamido L-Leu, be prepared into (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine N-ethanoyl-L-Leu salt.
10. the preparation method of an Apremilast; comprise the preparation method of formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine described in claim 1-8; it is characterized in that, also continue following steps:
Apremilast is prepared by making formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine and the condensation of 3-kharophen Tetra hydro Phthalic anhydride; Or:
Make formula (I) intermediate (S)-1-(3-oxyethyl group-4-methoxyl group) phenyl-2-methylsulfonyl ethamine and 3-kharophen Tetra hydro Phthalic anhydride and N-acetamido L-Leu react salify, then prepare Apremilast with the condensation of 3-kharophen Tetra hydro Phthalic anhydride.
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Denomination of invention: A Preparation Method for Synthesizing the Intermediate of Apste Effective date of registration: 20221213 Granted publication date: 20160706 Pledgee: Guangdong Development Bank Co.,Ltd. Dongying Branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2022980026441 |