CN114105946A - Tedizolid phosphate intermediate and preparation method thereof - Google Patents

Tedizolid phosphate intermediate and preparation method thereof Download PDF

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CN114105946A
CN114105946A CN202010867695.9A CN202010867695A CN114105946A CN 114105946 A CN114105946 A CN 114105946A CN 202010867695 A CN202010867695 A CN 202010867695A CN 114105946 A CN114105946 A CN 114105946A
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tetrahydrofuran
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张澎涛
吴亮
竺伟
甘立新
吕建国
陶伟锋
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SYNCOZYMES (SHANGHAI) CO Ltd
Zhejiang Supor Pharmaceuticals Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system

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Abstract

The invention discloses an intermediate of tedizolid phosphate and a preparation method thereof. The invention takes 3-fluoro-4-bromoaniline and disubstituted amine as starting materials to synthesize a tedizolid phosphate intermediate (compound I) so as to prepare the tedizolid phosphate. The method disclosed by the invention is simple to operate, high in yield and high in purity, and is suitable for industrial production.

Description

Tedizolid phosphate intermediate and preparation method thereof
The technical field is as follows:
the invention belongs to the field of pharmaceutical chemistry, and particularly relates to an intermediate for preparing tedizolid phosphate and a preparation method thereof.
Background art:
tedizolid Phosphate, chemical name of (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) 3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one dihydrogen Phosphate, English name of Tedizolid phospate, and trade name of Tedizolid phospate
Figure BDA0002650184880000013
(CAS No: 856867-55-5). Tedizolid phosphate isThe second generation of oxazolidinone antibiotics developed by Cubist corporation, and obtained FDA approval in the united states for marketing in 6 months of 2014, are mainly used for treating skin or tissue infections caused by gram-positive bacteria such as staphylococcus aureus and various streptococci. The tedizolid has high activity and wide antibacterial spectrum, the dosage of the tedizolid is one third of that of the first generation linezolid, and the tedizolid is expected to replace the first generation linezolid to market on a scale of nearly 15 hundred million dollars.
Figure BDA0002650184880000011
TRIUS THERAPEUTIC Inc. discloses a process for preparing tedizolid phosphate in patent CN102177156, the route is shown in Scheme 1.
Figure BDA0002650184880000012
Figure BDA0002650184880000021
According to the method, 3-fluoro-4-bromoaniline and benzyl chloroformate are used as starting materials to synthesize tedizolid phosphate, wherein the yield of a product 4- (benzyloxycarbonylamino) -2-fluorobenzeneboronic acid obtained by the second-step boronization reaction is only 66%, the purity is 89.8%, bromine impurities cannot be removed in the post-treatment process, the palladium catalytic residual amount in the third-step reaction is high, and the recovery rate of a palladium catalyst is only 18%. In addition, the total yield of the route is low, only about 40%, the efficiency is low, and the cost is high.
Therefore, we need to find new preparation routes or new intermediates for preparing tedizolid phosphate.
The invention content is as follows:
the invention aims to provide a novel tedizolid phosphate intermediate, a preparation method thereof and a method for preparing tedizolid phosphate by aiming at the defects of the prior art.
In one aspect, the invention provides a novel intermediate, a compound having the structure shown in formula I, or a pharmaceutically acceptable salt thereof,
Figure BDA0002650184880000022
wherein R is1And R2Each independently selected from C1-12Alkyl radical, C3-8Cycloalkyl, aryl or substituted aryl; or R1And R2With the attached N atom forming a 3-8 membered ring.
Further, in certain preferred embodiments, R1And R2Each independently selected from C1-6Alkyl, benzyl; or R1And R2Form a 5-or 6-membered heterocyclic ring with the attached N atom.
Still further, in certain preferred embodiments, R1And R2Each independently selected from methyl, ethyl, isopropyl, benzyl; r1And R2Form morpholine, N-methylpiperazine and the like with the attached N atom.
In another aspect, the present invention provides a process for preparing an intermediate of tedizolid phosphate (compound I), comprising the steps of:
Figure BDA0002650184880000031
step (1): 4-bromo-3-fluoroaniline (compound II) and disubstituted amine (compound III) are used as raw materials and react to generate a compound IV;
step (2): carrying out boronization reaction on the compound IV to obtain a compound V;
and (3): carrying out coupling reaction on the compound V and the compound VI to obtain a compound I;
further, in the step (1), 4-bromo-3-fluoroaniline (compound II), bis (trichloromethyl) carbonate and disubstituted amine (compound III) are used as raw materials to prepare a compound IV.
Further, in the step (2), the compound III is subjected to a boronizing reaction with a boronizing reagent to obtain a compound V, wherein the boronizing reagent is triisopropyl borate, trimethyl borate or triethyl borate, and preferably triisopropyl borate.
Further, in the step (3), the compound V and 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine are subjected to coupling reaction under the catalysis of palladium to obtain a compound I.
Further, the step (3) is carried out for 12 hours at the temperature of 50-80 ℃.
On the other hand, the compound shown in the formula I can be used for preparing tedizolid or tedizolid phosphate, and the specific scheme is as follows:
Figure BDA0002650184880000041
deprotecting the compound I to obtain a compound VII; then reacting with benzyl chloroformate to obtain a compound VIII; then cyclizing with compound IX to obtain tedizolid, and finally phosphorylating to obtain compound X.
The invention has the beneficial effects that the invention provides an intermediate (compound I) of tedizolid phosphate and a preparation method thereof. The reaction yield of the second step can reach 85 percent, the purity is 97 percent, compared with the technical route of the original research company, the impurities in the process of the second step are obviously reduced, and the yield and the purity are greatly improved. In the invention, the compound I can be directly separated out after the third step of reaction is finished, the post-treatment process is simplified, the operation of removing palladium by recrystallization is reduced, the product yield is improved, and the recovery of palladium in the mother liquor is facilitated. The method has the advantages of simple operation, high yield, high purity and low cost, and is suitable for industrial production.
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FIG. 1 Compound IV (R) in example 11Methyl, R2Methyl) of1H NMR
FIG. 2 Compound V (R) of example 21Methyl, R2Methyl) of1H NMR
FIG. 3 Compound I (R) of example 31Methyl, R2Methyl) of1H NMR
Detailed Description
The technical content of the present invention is further described below with reference to specific examples for better understanding of the content of the present invention, but the scope of the present invention is not limited thereto.
EXAMPLE 1 preparation of Compound IV (R)1Methyl, R2Armenine methyl
5.0g of 4-bromo-3-fluoroaniline, 3.12g of bis (trichloromethyl) carbonate and 30mL of tetrahydrofuran were mixed and dissolved in a 100mL three-necked flask; mixing 5.87g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 14.5mL of 2.0M dimethylamine tetrahydrofuran solution into the reaction solution, reacting for 1 hour at the temperature of 0-5 ℃, and carrying out aftertreatment to obtain the title compound, wherein the yield is 96%, and the purity is 99.5%.1The H NMR spectrum is shown in FIG. 1.
EXAMPLE 2 preparation of Compound V (R)1Methyl, R2Armenine methyl
Adding 0.5g of the compound IV obtained in example 1, 0.72g of triisopropyl borate and 5mL of tetrahydrofuran into a 25mL three-necked flask, mixing, dissolving, cooling to-78 ℃, adding 1.5mL of 2.5M n-butyllithium, reacting for 2 hours, and carrying out aftertreatment after the reaction is finished to obtain the title compound with the yield of 85%; the purity is 97%.1The H NMR spectrum is shown in FIG. 2.
EXAMPLE 3 preparation of Compound I (R)1Methyl, R2Armenine methyl
A25 mL three-necked flask was charged with 0.2g of Compound V obtained in example 2 and 0.106g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine (Compound VI) and 3mL of tetrahydrofuran to mix the eluates; 0.025g of tetratriphenylphosphine palladium, 0.122g of potassium carbonate and 0.5L of water were added under nitrogen protection, the reaction temperature was raised to 60 ℃ for 12 hours, and after completion of the reaction, the title compound was obtained by post-treatment in 97% yield and 98% purity.1The H NMR spectrum is shown in FIG. 3.
EXAMPLE 4 preparation of Compound VII
0.5g of the compound I obtained in example 3, 10mL of dioxane and 2.5mL of deionized water were added to a 25mL three-necked flask, mixed, 0.1g of lithium hydroxide was added, the temperature was raised to 90 ℃ to react for 20 hours, and the title compound was obtained by workup in 99% yield and 98% purity.
EXAMPLE 5 preparation of Compound IV (R)1Ethyl, R2Becoming ethyl)
5.0g of 4-bromo-3-fluoroaniline, 3.12g of bis (trichloromethyl) carbonate and 30mL of methylene chloride are mixed and dissolved in a 100mL three-necked flask; mixing 5.87g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 15mL of 2.0M diethylamine dichloromethane solution into the reaction solution, reacting for 1 hour at the temperature of 0-5 ℃, and carrying out post-treatment to obtain the title compound.
EXAMPLE 6 preparation of Compound V (R)1Ethyl, R2Becoming ethyl)
A25 mL three-necked flask was charged with 0.5g of compound IV obtained in example 5, 0.72g of trimethyl borate and 5mL of methylene chloride, mixed and dissolved, cooled to-78 deg.C, and 1.5mL of 2.5M n-butyllithium was added thereto, followed by reaction for 2 hours, TLC monitoring, completion of the reaction, and post-treatment to obtain the titled compound.
EXAMPLE 7 preparation of Compound I (R)1Ethyl, R2Becoming ethyl)
A25 mL three-necked flask was charged with 0.2g of Compound V obtained in example 6 and 0.106g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine and 3mL of tetrahydrofuran to mix; 0.025g of tetratriphenylphosphine palladium, 0.122g of potassium carbonate and 0.5mL of water were added under nitrogen, the reaction temperature was raised to 60 ℃ to react for 12 hours, and after the reaction was completed, the title compound was obtained by post-treatment.
EXAMPLE 8 preparation of Compound VII
In a 25mL three-necked flask, 0.5g of the compound I obtained in example 7 was added, mixed with 10mL of dioxane and 2.5mL of deionized water, and 0.1g of lithium hydroxide was added, and the mixture was heated to 90 ℃ to react for 20 hours, followed by workup to obtain the title compound.
EXAMPLE 9 preparation of Compound IV (R)1Is isopropyl, R2As isopropyl group)
5.0g of 4-bromo-3-fluoroaniline, 3.2g of bis (trichloromethyl) carbonate and 30mL of tetrahydrofuran were mixed and dissolved in a 100mL three-necked flask; mixing 6g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 17mL of 2.0M diisopropylamine tetrahydrofuran solution into the reaction solution, reacting for 1 hour at the temperature of 0-5 ℃, and carrying out aftertreatment to obtain the title compound.
EXAMPLE 10 preparation of Compound V (R)1Is isopropyl, R2As isopropyl group)
A25 mL three-necked flask was charged with 0.5g of compound IV obtained in example 9, 0.8g of triethyl borate and 5mL of tetrahydrofuran, and the mixture was cooled to-78 deg.C, and 1.5mL of 2.5M n-butyllithium was added thereto, followed by 2 hours of reaction, TLC monitoring, completion of the reaction, and post-treatment to obtain the titled compound.
EXAMPLE 11 preparation of Compound I (R)1Is isopropyl, R2As isopropyl group)
A25 mL three-necked flask was charged with 0.2g of Compound V obtained in example 10 and 0.15g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine and 3mL of tetrahydrofuran to mix the eluates; 0.03g of tetrakistriphenylphosphine palladium, 0.13g of potassium carbonate and 0.5mL of water were added under nitrogen protection, the reaction temperature was raised to 60 ℃ to react for 12 hours, and after the reaction was completed, the title compound was obtained by post-treatment.
EXAMPLE 12 preparation of Compound VII
In a 25mL three-necked flask, 0.5g of the compound I obtained in example 11 was added, mixed with 10mL of dioxane and 2.5mL of deionized water, and 0.1g of lithium hydroxide was added, and the mixture was heated to 90 ℃ to react for 20 hours, followed by workup to obtain the title compound.
EXAMPLE 13 preparation of Compound IV (R)1Is benzyl, R2Artesunate benzyl group
5.0g of 4-bromo-3-fluoroaniline, 3.12g of bis (trichloromethyl) carbonate and 30mL of tetrahydrofuran were mixed and dissolved in a 100mL three-necked flask; mixing 5.87g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 19mL of 2.0M dibenzylamine tetrahydrofuran solution into the reaction solution, reacting for 1 hour at the temperature of 0-5 ℃, and carrying out post-treatment to obtain the title compound.
EXAMPLE 14 preparation of Compound V (R)1Is benzyl, R2Artesunate benzyl group
A25 mL three-necked flask was charged with 0.5g of compound IV obtained in example 13, 0.8g of triisopropyl borate and 5mL of tetrahydrofuran, mixed and dissolved, cooled to-78 deg.C, and then 1.5mL of 2.5M n-butyllithium was added thereto, reacted for 2 hours, followed by TLC monitoring and completion of the reaction, followed by workup to obtain the titled compound.
EXAMPLE 15 preparation of Compound I (R)1Is benzyl, R2Artesunate benzyl group
A25 mL three-necked flask was charged with 0.2g of compound V obtained in example 14 and 0.2g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine and 3mL of tetrahydrofuran to mix well; 0.03g of tetrakistriphenylphosphine palladium, 0.15g of potassium carbonate and 0.5mL of water were added under nitrogen protection, the reaction temperature was raised to 60 ℃ to react for 12 hours, and after the reaction was completed, the title compound was obtained by post-treatment.
EXAMPLE 16 preparation of Compound VII
In a 25mL three-necked flask, 0.5g of the compound I obtained in example 15, 10mL of dioxane and 2.5mL of deionized water were added, mixed, and 0.1g of lithium hydroxide was added, and the mixture was heated to 90 ℃ to react for 20 hours, followed by workup to obtain the title compound.
EXAMPLE 17 preparation of Compound IV (Compound III is morpholine)
5.0g of 4-bromo-3-fluoroaniline, 3.2g of bis (trichloromethyl) carbonate and 30mL of tetrahydrofuran were mixed and dissolved in a 100mL three-necked flask; mixing 5.8g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 20mL of 2.0M morpholine tetrahydrofuran solution into the reaction solution, reacting for 1 hour at the temperature of 0-5 ℃, and carrying out aftertreatment to obtain the title compound.
EXAMPLE 18 preparation of Compound V (Compound III is morpholine)
A25 mL three-necked flask was charged with 0.5g of compound IV obtained in example 17, 0.72g of triisopropyl borate and 5mL of tetrahydrofuran, mixed and dissolved, cooled to-78 deg.C, and then 1.5mL of 2.5M n-butyllithium was added thereto, reacted for 2 hours, followed by TLC monitoring and post-treatment to obtain the titled compound.
EXAMPLE 19 preparation of Compound I (Compound III is morpholine)
A25 mL three-necked flask was charged with 0.2g of compound V obtained in example 18 and 0.2g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine and 3mL of tetrahydrofuran to mix; 0.03g of tetrakistriphenylphosphine palladium, 0.15g of potassium carbonate and 0.5mL of water were added under nitrogen protection, the reaction temperature was raised to 60 ℃ to react for 12 hours, and after the reaction was completed, the title compound was obtained by post-treatment.
EXAMPLE 20 preparation of Compound VII
In a 25mL three-necked flask, 0.5g of the compound I obtained in example 19 was added, mixed with 10mL of dioxane and 2.5mL of deionized water, and 0.1g of lithium hydroxide was added, and the mixture was heated to 90 ℃ to react for 20 hours, followed by workup to obtain the title compound.
EXAMPLE 21 preparation of Compound IV (Compound III is N-methylpiperazine)
5.0g of 4-bromo-3-fluoroaniline, 3.12g of bis (trichloromethyl) carbonate and 30mL of tetrahydrofuran were mixed and dissolved in a 100mL three-necked flask; mixing 5.87g of triethylamine and 30mL of tetrahydrofuran, dropwise adding the mixture into the reaction solution, controlling the temperature to be 0-5 ℃, reacting for 3 hours, then adding 20mL of 2.0M N-methylpiperazine tetrahydrofuran solution into the reaction solution, reacting for 2 hours at the temperature of 0-5 ℃, and carrying out aftertreatment to obtain the title compound.
EXAMPLE 22 preparation of Compound V (Compound III is N-methylpiperazine)
A25 mL three-necked flask was charged with 0.5g of the compound IV obtained in example 21, 0.72g of triisopropyl borate and 5mL of tetrahydrofuran, and the mixture was cooled to-78 deg.C, and 2mL of 2.5M n-butyllithium was added thereto for 3 hours, followed by TLC monitoring and completion of the reaction, followed by workup to obtain the titled compound.
EXAMPLE 23 preparation of Compound I (Compound III is N-methylpiperazine)
A25 mL three-necked flask was charged with 0.2g of compound V obtained in example 22 and 0.12g of 5-bromo-2- (2-methyl-2H-tetrazol-5-yl) -pyridine and 3mL of tetrahydrofuran to mix; 0.03g of tetrakistriphenylphosphine palladium, 0.15g of potassium carbonate and 0.5mL of water were added under nitrogen protection, the reaction temperature was raised to 60 ℃ to react for 12 hours, and after the reaction was completed, the title compound was obtained by post-treatment.
EXAMPLE 24 preparation of Compound VII
In a 25mL three-necked flask, 0.5g of the compound I obtained in example 23, 10mL of dioxane and 2.5mL of deionized water were added, mixed, and 0.1g of lithium hydroxide was added, and the mixture was heated to 90 ℃ to react for 20 hours, followed by workup to obtain the title compound.
EXAMPLE 25 preparation of Compound VIII
0.5g of the compound VII obtained in example 4 and 10mL of tetrahydrofuran were added to a 25mL three-necked flask, mixed, and sodium carbonate was added; and (3) cooling to 0-5 ℃, dropwise adding 0.4g of benzyl chloroformate into the reaction solution, reacting for 2 hours, and carrying out post-treatment to obtain the title compound.
EXAMPLE 26 preparation of Compound X
The same as CN102177156(B) in example 6.
EXAMPLE 27 preparation of Compound I
The same as CN102177156(B) in example 7.

Claims (3)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,
Figure FDA0002650184870000011
wherein R is1And R2Each independently selected from C1-12Alkyl radical, C3-8Cycloalkyl, aryl or substituted aryl; or R1And R2With the attached N atom forming a 3-8 membered ring.
2. A preparation method of a compound shown in a formula I is characterized in that the preparation route is shown as follows;
Figure FDA0002650184870000012
wherein R is1And R2The definition of (A) is as above.
3. A compound according to claim 1, wherein the compound is useful for the preparation of tedizolid or tedizolid phosphate.
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CN105111237A (en) * 2015-09-14 2015-12-02 成都维恒医药科技有限公司 Method for compounding tedizolid phosphate
CN105859780A (en) * 2015-01-21 2016-08-17 山东康美乐医药科技有限公司 Method for preparing tedizolid phosphate
CN106632298A (en) * 2015-11-03 2017-05-10 上海科胜药物研发有限公司 Preparation method of tedizolid and intermediate of tedizolid
CN110938058A (en) * 2018-09-22 2020-03-31 南京优科生物医药研究有限公司 Preparation method of oxazolidinone antibiotic intermediate

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Publication number Priority date Publication date Assignee Title
CN102177156A (en) * 2008-10-10 2011-09-07 特留斯治疗学公司 Methods for preparing oxazolidinones and compositions containing them
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