CN113072471A - Lifeiste intermediate and preparation method thereof - Google Patents
Lifeiste intermediate and preparation method thereof Download PDFInfo
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- CN113072471A CN113072471A CN202110229211.2A CN202110229211A CN113072471A CN 113072471 A CN113072471 A CN 113072471A CN 202110229211 A CN202110229211 A CN 202110229211A CN 113072471 A CN113072471 A CN 113072471A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/48—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
Abstract
The invention relates to the field of pharmaceutical chemical production, and discloses a lifaste intermediate and a preparation method thereof, wherein the reaction route of the preparation method is as follows:
Description
Technical Field
The invention relates to the field of pharmaceutical chemical production, and particularly relates to a lifaste intermediate and a preparation method thereof.
Background
Lifiteast (lifitegrant) is a drug developed by Shire for the treatment of dry eye, marketed in the united states by the U.S. Food and Drug Administration (FDA) approved 7/11/2016, and due 5/17/2026 for the indication patent. The structural formula is as follows:
m-methylsulfonyl-L-phenylalanine is one of the main intermediates of liffetiliast.
First, chinese patent application publication No. CN104797574A discloses two methods for synthesizing m-methylsulfonyl-L-phenylalanine:
a. the synthesis route takes 3-bromo-L-phenylalanine as a starting material, and the starting material is protected by a protecting group, substituted by methylsulfonyl, and then the protecting group is removed.
b. 3-methylsulfonyl benzaldehyde is used as an initial raw material, an intermediate is obtained through three steps of reactions, a noble metal catalyst and a ligand are used for asymmetric hydrogenation in the route, the cost is high, and the chiral purity is not high.
Secondly, chinese patent application publication No. CN106947792A discloses a method of m-methylsulfonyl-L-phenylalanine:
the method uses 3-bromobenzaldehyde as an initial raw material, obtains an intermediate through four-step reaction, uses a noble metal catalyst for hydrogenation in the route, has high cost and is not suitable for amplification.
Further, chinese patent application publication No. CN111471003A discloses a method of producing m-methylsulfonyl-L-phenylalanine:
the method takes 3-methylsulfonyl bromobenzene as a starting material, and the route uses noble metal and heavy metal for coupling reaction, so that the cost is high, and the method is not suitable for industrialization.
Disclosure of Invention
In view of the above disadvantages in the prior art, the first objective of the present invention is to provide a preparation method of a lifaste intermediate, wherein the synthesis method has characteristics of simple operation, stable and reliable process, and safe production, and is suitable for industrial production.
The second purpose of the invention is to provide the liflstet intermediate prepared by the method, the product conversion rate is high, and the purity of the liflstet intermediate is high.
In order to achieve the above purpose, the solution adopted by the invention is as follows:
a liflstet intermediate (m-methylsulfonyl-L-phenylalanine) of the formula:
a preparation method of a liflstet intermediate comprises the following steps:
s1, reacting a compound of a formula I and methyl sulfonate serving as raw materials in the presence of an alkali and an organic catalyst to generate an intermediate of a formula II;
s2, reacting the compound shown in the formula II in the presence of a halogenating agent, AIBN and an organic solvent A to generate an intermediate shown in the formula III;
s3, reacting the compound shown in the formula III with diethyl acetylaminomalonate in the presence of alkali and an organic solvent B to generate an intermediate shown in a formula IV;
s4, deprotecting the compound shown in the formula IV under an acidic condition, and reacting to generate an intermediate shown in the formula V;
s5, reacting the compound shown in the formula V with a methyl ester compound under the condition of a catalyst to generate an intermediate shown in a formula VI;
s6, reacting the compound shown in the formula VI with an acetyl compound under an alkaline condition to generate an intermediate shown in the formula VII;
s7, reacting the compound shown in the formula VII under the condition of chiral induction enzyme to generate the compound shown in the formula VIII;
s8, hydrolyzing the compound shown in the formula VIII under an alkaline condition to obtain a compound shown in the formula IX, namely a key intermediate of the lifaste: m-methylsulfonyl-L-phenylalanine.
The reaction route is as follows:
preferably, in S1, the catalyst is BPO or AIBN, most preferably AIBN.
Preferably, in S2, the halogenating agent is one or more of NCS, NBS or NIS, most preferably NBS.
Preferably, in S3, the molar ratio of diethyl acetamidomalonate to the compound of formula III is 1-1.5:1, most preferably 1.1: 1; the molar ratio of the base to the compound of formula III is 1.2-2:1, most preferably 1.2: 1.
Preferably, in S3, the base is one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide, potassium carbonate or sodium hydroxide, most preferably sodium ethoxide; the organic solvent is one or more of DMF, THF, toluene, ethanol or methanol, and ethanol is the most preferable; the reaction temperature is 50-120 deg.C, most preferably 65 deg.C.
Preferably, X in the compound of formula III is one of Cl, Br or I, most preferably Br.
Preferably, in S4, the acid used in the acidic condition is hydrochloric acid or trifluoroacetic acid, most preferably hydrochloric acid.
Preferably, in S5, the catalyst is thionyl chloride or concentrated sulfuric acid, most preferably thionyl chloride.
Preferably, in S6, the base used in the basic condition comprises one or more of potassium carbonate, sodium hydroxide or triethylamine, and most preferably sodium hydroxide; the acetyl compound comprises: acetic anhydride or acetyl chloride, most preferably acetic anhydride.
Preferably, in S8, the alkali used in the alkaline condition comprises one or more of sodium hydroxide, lithium hydroxide or potassium hydroxide, and most preferably sodium hydroxide.
The invention has the beneficial effects that:
1. the synthesis method of the liffetid intermediate is simple to operate, stable and reliable in process and good in safety, can obviously inhibit the generation of byproducts, does not cause excessive pollution to the environment, and is suitable for industrial production.
2. The invention has the advantages of easily obtained raw materials and auxiliary materials, low price, no heavy metal or noble metal substances adopted in the synthesis process, low cost, high chiral purity and short period compared with the existing production route.
3. The invention has the advantages of good synthesis reaction selectivity, higher conversion rate and high purity of the obtained liflstet intermediate.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The liflstett intermediate and the preparation method thereof provided by the embodiments of the present invention are specifically described below.
Example 1: synthesis of intermediate formula II:
a 2L three-necked flask is sequentially added with m-bromobenzene toluene (85.5g,0.5mol,1eq), sodium methanesulfonate (61.2g,0.6mol,0.6eq), cuprous iodide (4.5g), sodium tert-butoxide (72g,0.75mol,1.5eq), 800ml of dry DMF, nitrogen protection, reaction at 110 ℃ overnight, TLC controlled and complete reaction; and (3) post-treatment: the reaction solution was cooled to 0-5 ℃, 600ml of ice water was added, ethyl acetate (300 ml. x.3) was added, the organic phases were combined, 500ml of water and 500ml of saturated sodium chloride were used for the organic phase, the organic phase was dried, filtered and concentrated under reduced pressure to give an oil which was recrystallized from petroleum ether to give 77g of a yellow solid with a yield of 90% and a purity of 98.5%.
Example 2: synthesis of intermediate formula III:
A2L three-necked flask was charged with the formula II (85g,0.5mol, 1eq) obtained in example 1 and 600ml of chloroform in that order, with stirring turned on, NBS (106.8g, 0.6mol,1.2eq) and AIBN (8.2g,0.05mol,0.1eq) were added at 20-25 ℃ for 5h with stirring, TLC was monitored, and after completion of the reaction, post-treatment: 300ml of 10% sodium hydrogen sulfite was added, the organic phase was extracted with 300ml of water and saturated sodium chloride, respectively, the organic phase was dried, filtered and concentrated to obtain 112.05g of yellow oil with a yield of 90% and a purity of 95.4%.
Example 3: synthesis of intermediate formula III:
the present embodiment is different from embodiment 2 in that: selecting NCS as a halogenating reagent, BPO as a catalyst and carbon tetrachloride as an organic solvent A; other reaction conditions were the same as in example 2; the product was obtained in 86% yield and 98.60% purity.
Example 4: synthesis of intermediate formula IV:
adding diethyl acetamidomalonate (120g, 0.55mol,1.1eq) and 500ml of absolute ethyl alcohol into a 2L three-necked flask in sequence, cooling to 0-5 ℃, slowly dropwise adding a 20% sodium ethoxide ethanol solution (205ml,0.6mol,1.2eq), stirring at room temperature for 2 hours, slowly dropwise adding III (124.5g, 0.5mol) obtained in example 2, dissolving in 100ml of absolute ethyl alcohol, heating to 60-65 ℃ after the addition is finished, reacting for 3-6 hours, performing TLC (thin layer chromatography) central control, and performing aftertreatment: the reaction was directly concentrated to an oil and used in the next step.
Example 5: synthesis of intermediate formula IV:
this embodiment is different from embodiment 4 in that: the compound of formula III obtained in example 3 was prepared by reacting diethyl acetylaminomalonate in 0.7mol, potassium carbonate (1mol) as the base and DMF as the organic solvent B under the same conditions as in example 4.
Example 6: synthesis of intermediate formula V:
A2L three-necked flask is sequentially added with the reaction solution of the formula IV obtained in example 4, 800ml of 12M HCl is added, the reaction is refluxed and reacted overnight, TLC is controlled and post-treatment is carried out: and (3) cooling to 0-5 ℃, separating out solids, filtering, and leaching a filter cake with ice water to obtain 99.6g of white solids, wherein the yield is 84%, and the purity is 99.5%.
Example 7: synthesis of intermediate formula V:
this embodiment is different from embodiment 6 in that: selecting the compound of formula IV obtained in example 5 and acid as trifluoroacetic acid, and carrying out the same reaction conditions as in example 6; the yield of the product was 70% and the purity was 97.00%.
Example 8: synthesis of intermediate of formula VI:
A2L three-necked flask is sequentially added with the formula V (139.5g,0.5mol) obtained in example 6 and 1.2L methanol, thionyl chloride (178.5g,0.75mol,1.5eq) is slowly added dropwise at room temperature, then the temperature is raised to 45-55 ℃, the reaction is carried out overnight, TLC is controlled, and after the reaction is finished, the post-treatment is carried out: the reaction solution was concentrated to obtain 125.9g of a pale yellow solid, yield 98%, purity 99.6%.
Example 9: synthesis of intermediate of formula VI:
the present embodiment is different from embodiment 8 in that: selecting the compound of formula V obtained in example 7 and a catalyst as concentrated sulfuric acid; other reaction conditions were the same as in example 8; the yield of the product was 92% with a purity of 98.7%.
Example 10: synthesis of intermediate of formula VII:
VI (128.5.5g,0.5mol) obtained in example 8, 1.25L THF and 140ml water were added in a 2L three-necked flask in this order, stirred at room temperature, adjusted to PH 8-9 by the addition of 20% aqueous sodium hydroxide, acetic anhydride (56.1g,0.55mol,1.1eq) was slowly added dropwise, the PH was maintained at 8-9 with care taken to monitor the PH, and after addition, the reaction was carried out at room temperature for 4-6h, controlled by TLC, and after completion of the reaction, worked up: 500ml of water was added, pH was adjusted to 1-2, the reaction mixture was concentrated under reduced pressure to remove THF, 3 × 500ml of EA was added for extraction, the organic phase was extracted with 200ml of saturated sodium chloride, the liquid was separated, the organic phase was dried, filtered and concentrated to obtain 127g of a white solid, yield 85%, purity 99.3%.
Example 11: synthesis of intermediate of formula VII:
the present embodiment is different from embodiment 10 in that: selecting the compound of formula VI obtained in example 9, potassium carbonate as base, acetyl chloride as acetyl reagent; other reaction conditions were the same as in example 10; the product was obtained in 83% yield and 98.5% purity.
Example 12: synthesis of intermediate of formula VIII
A2L three-necked flask was charged with the formula VII (149.5g, 0.5mol) obtained in example 10, 1.5L of THF and 150ml of water in this order, stirred at room temperature, and then 10% aqueous ammonia was added to adjust the reaction solution to pH 7-7.5, and the reaction solution of the formula VI was completely dissolvedAfter the hydrolysis, 7.5g L-acetamidohydrolase was added, the temperature was controlled at 35-39 ℃ and the pH was 7-7.5, the reaction was carried out overnight, the HPLC control was carried out, and the workup: filtering, leaching the solid with water, and drying to obtain 41g of white solid, wherein the yield is 65%, and the purity is as follows: 99.6%, ee value 99.98%. ESI-MS (M/z): M + H+)258.10。
Example 13: synthesis of intermediate of formula IX
A 2L three-necked flask was charged with formula VIII obtained in example 12 (128.5g), 500ml THF and 500ml water in that order, 160ml was added with 25% sodium hydroxide solution, stirred at room temperature, controlled by TLC, post-treated, adjusted to PH 6-7 with 6M hydrochloric acid, a large amount of solid precipitated, filtered, rinsed with water, and dried to give 111.7g, yield 99.2%, purity: 99.7%, ee value 99.98%.
1H-NMR(400MHz，DMSO)δ:2.95(s,3H)，2.90(d,1H),3.16(d,1H)，3.89(t,1H)，7.3(d,1H)，7.64(t,1H)，7.85(s,1H)，7.95(d,1H)。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A preparation method of a liflstet intermediate is characterized by comprising the following steps:
s1, taking a compound of a formula I and methylsulfonate as raw materials, and reacting in the presence of an alkali and an organic catalyst to generate an intermediate of a formula II, wherein the reaction equation is as follows:
s2, reacting the compound shown in the formula II in the presence of a halogenating reagent, a catalyst and an organic solvent A to generate an intermediate shown in the formula III, wherein the reaction equation is as follows:
s3, reacting the compound shown in the formula III with diethyl acetylaminomalonate in the presence of alkali and an organic solvent B to generate an intermediate shown in a formula IV, wherein the reaction equation is as follows:
s4, deprotecting the compound shown in the formula IV under an acidic condition, and reacting to generate an intermediate shown in the formula V, wherein the reaction equation is as follows:
s5, reacting the compound shown in the formula V with a methyl ester compound under the condition of a catalyst to generate an intermediate shown in the formula VI, wherein the reaction equation is as follows:
s6, reacting the compound shown in the formula VI with an acetyl compound under an alkaline condition to generate an intermediate shown in the formula VII, wherein the reaction equation is as follows:
s7, reacting the compound in the formula VII under the condition of chiral induction enzyme to generate the compound in the formula VIII, wherein the reaction equation is as follows:
s8, hydrolyzing the compound shown in the formula VIII under alkaline conditions to obtain a compound shown in the formula IX, wherein the reaction equation is as follows:
2. the method of claim 1, wherein in S1 the catalyst is BPO or AIBN.
3. The method for preparing the liffetid intermediate according to claim 1, wherein in S2, the halogenating agent is one or more of NCS, NBS or NIS.
4. The method for preparing the liffetiliast intermediate as claimed in claim 1, wherein the molar ratio of diethyl acetamidomalonate to the compound of formula III in S3 is 1-1.5: 1.
5. The method for preparing the liffetiliast intermediate as claimed in claim 1, wherein the molar ratio of the base to the compound of formula III in S3 is 1.2-2: 1.
6. The method for preparing a liffetiliast intermediate as claimed in claim 1, wherein in S4, the acid used in the acidic condition is hydrochloric acid or trifluoroacetic acid.
7. The method for preparing the liffetid intermediate as claimed in claim 1, wherein in S5, the catalyst is thionyl chloride or concentrated sulfuric acid.
8. The method for preparing the liffetid intermediate as claimed in claim 1, wherein in S6, the acetyl compound comprises: acetic anhydride or acetyl chloride.
9. The preparation method of the liffetid intermediate as claimed in claim 1, wherein in S8, the alkali used in the alkaline condition comprises one or more of sodium hydroxide, lithium hydroxide or potassium hydroxide.
10. A liflstetter intermediate is characterized by comprising an intermediate compound shown as a formula II, an intermediate compound shown as a formula III, an intermediate compound shown as a formula IV, an intermediate compound shown as a formula V, an intermediate compound shown as a formula VI, an intermediate compound shown as a formula VII or an intermediate compound shown as a formula IX.
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