The present disclosure is directed synthetic methods for the preparation of 4-valyloxybutyric acid. The synthetic methods described herein employ a diverse array of protecting group strategies and reaction conditions. Additionally, the present disclosure is directed to compounds useful as synthetic intermediates in the preparation of 4-valyloxybutyric acid.

The present disclosure is directed synthetic methods for the preparation of 4-valyloxybutyric acid. The synthetic methods described herein employ a diverse array of protecting group strategies and reaction conditions. Additionally, the present disclosure is directed to compounds useful as synthetic intermediates in the preparation of 4-valyloxybutyric acid.

The present disclosure is directed synthetic methods for the preparation of 4-valyloxybutyric acid. The synthetic methods described herein employ a diverse array of protecting group strategies and reaction conditions. Additionally, the present disclosure is directed to compounds useful as synthetic intermediates in the preparation of 4-valyloxybutyric acid.

A method of forming a chelating composition includes the steps of: providing a first mixture comprising water and a tetrasodium salt of glutamic acid N,N-diacetic acid and having a pH of greater than about 10; and acidifying the first mixture via ion exchange and/or bipolar membrane electrodialysis to reduce a pH of the chelating composition to a pH of at least about 9; wherein the chelating composition comprises the tetrasodium salt of glutamic acid N,N-diacetic acid in an amount of at least about 50 weight percent based on a total weight of the chelating composition as determined using an Fe-Total Sequestering Value; and wherein the chelating composition has a viscosity of less than about 1350 mPa.Math.s measured at about 5° C., or less than about 350 mPa.Math.s measured at about 20° C., each using a Brookfield DV II plus viscometer with spindle S18 and a temperature controlled bath.

A method of forming a chelating composition includes the steps of: providing a first mixture comprising water and a tetrasodium salt of glutamic acid N,N-diacetic acid and having a pH of greater than about 10; and acidifying the first mixture via ion exchange and/or bipolar membrane electrodialysis to reduce a pH of the chelating composition to a pH of at least about 9; wherein the chelating composition comprises the tetrasodium salt of glutamic acid N,N-diacetic acid in an amount of at least about 50 weight percent based on a total weight of the chelating composition as determined using an Fe-Total Sequestering Value; and wherein the chelating composition has a viscosity of less than about 1350 mPa.Math.s measured at about 5° C., or less than about 350 mPa.Math.s measured at about 20° C., each using a Brookfield DV II plus viscometer with spindle S18 and a temperature controlled bath.

A method includes combining monosodium glutamate and/or glutamic acid with formaldehyde to form a first combination; adding hydrogen cyanide to form a second combination comprising a monosodium salt of glutamic acid diacetonitrile, a cyclic GLMN, and a sodium salt of glutamic acid N-monoacetonitrile, maintaining a temperature of the second combination at less than about 16° C. and a pH of less than about 7; converting nitrile groups to carboxylate groups thereby forming a third combination comprising water and at least about 47 weight percent of the tetrasodium salt of GLDA, wherein a reaction yield is at least about 91%; providing a fourth combination comprising water and the tetrasodium salt of GLDA and having a pH of less than about 7; and combining the third and fourth combinations to form the chelating composition.

A method includes combining monosodium glutamate and/or glutamic acid with formaldehyde to form a first combination; adding hydrogen cyanide to form a second combination comprising a monosodium salt of glutamic acid diacetonitrile, a cyclic GLMN, and a sodium salt of glutamic acid N-monoacetonitrile, maintaining a temperature of the second combination at less than about 16° C. and a pH of less than about 7; converting nitrile groups to carboxylate groups thereby forming a third combination comprising water and at least about 47 weight percent of the tetrasodium salt of GLDA, wherein a reaction yield is at least about 91%; providing a fourth combination comprising water and the tetrasodium salt of GLDA and having a pH of less than about 7; and combining the third and fourth combinations to form the chelating composition.

This disclosure provides a chelating composition having a pH of at least about 9 and comprising: water; and the tetrasodium salt of glutamic acid N,N-diacetic acid present in an amount of at least about 50 weight percent based on a total weight of the chelating composition as determined using an Fe-Total Sequestering Value, wherein the chelating composition has a viscosity of less than about 1350 mPa.Math.s measured at about 5° C., or less than about 350 mPa.Math.s measured at about 20° C., each using a Brookfield DV II plus viscometer with spindle S18 and a temperature controlled bath.

This disclosure provides a chelating composition having a pH of at least about 9 and comprising: water; and the tetrasodium salt of glutamic acid N,N-diacetic acid present in an amount of at least about 50 weight percent based on a total weight of the chelating composition as determined using an Fe-Total Sequestering Value, wherein the chelating composition has a viscosity of less than about 1350 mPa.Math.s measured at about 5° C., or less than about 350 mPa.Math.s measured at about 20° C., each using a Brookfield DV II plus viscometer with spindle S18 and a temperature controlled bath.

Disclosed in the present invention are an aromatic vinyl or aromatic ethyl derivative, a preparation method therefor, an intermediate, a pharmaceutical composition, and an application. The aromatic vinyl or aromatic ethyl derivative in the present invention is as represented by general formula (I). The aromatic vinyl or aromatic ethyl derivative in the present invention has an obvious inhibitory effect on PD-1/PD-L1, is a very effective small-molecule PD-1/PD-L1 inhibitor, and can effectively alleviate or treat relevant diseases such as cancer.

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