Method for producing polyalkylene glycol derivative having amino group at end

• US 10,377,775 B2
• Filed: 12/04/2015
• Issued: 08/13/2019
• Est. Priority Date: 12/04/2014
• Status: Active Grant

• Current Assignee: Shin-Etsu Chemical Company Limited
• Original Assignee: Shin-Etsu Chemical Company Limited
• Inventors: Suka, Yuki, Harada, Yuji, Watanabe, Takeru, Nonaka, Shiori
• Primary Examiner(s): Brooks, Clinton A
• Assistant Examiner(s): Adzamli, Kofi
• Application Number:
  US14/959,088
• Publication Number:
  US 20160159831A1
• Time in Patent Office: 1,348 Days
• Field of Search: 556423
• CPC Class Codes: C07F 7/0892 Compounds with a Si-O-N linkage
• CPC Class Codes: C07F 7/10 containing nitrogen having a Si-N linkage
• CPC Class Codes: C08G 65/12 containing organo-metallic compounds or metal hydrides
• CPC Class Codes: C08G 65/2609 containing aliphatic hydroxyl groups
• CPC Class Codes: C08G 65/33303 containing amino group
• CPC Class Codes: C08G 65/33306 acyclic
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

A method simply produces a narrowly distributed and high-purity polyalkylene glycol derivative having an amino group at an end without using a heavy metal catalyst. A method for producing a polyalkylene glycol derivative having an amino group at the end by reacting a compound represented by the general formula (V) with an alkylene oxide, then reacting a reaction product with an electrophile represented by the general formula (I), and deprotecting the obtained product without using a heavy metal:
R_A³O(R_A⁴O)_k-1R_A⁴O⁻M⁺  (V)

• • wherein R_A³ represents a linear, branched, or cyclic hydrocarbon group having 1 to 20 carbon atoms; R_A⁴ represents an alkylene group having 2 to 8 carbon atoms; k represents an integer of 2 to 5; and M represents an alkali metal;

• • wherein R_A^1a and R_A^1b each independently represent a protective group of the amino group, or one of R_A^1a and R_A^1b represents H and the other represents a protective group of the amino group, or R_A^1a and R_A^1b bind to each other to form a cyclic protective group, and the protective group is deprotectable without using a heavy metal; R_A² represents a linear, branched, or cyclic hydrocarbon group having 1 to 6 carbon atoms; and X represents a leaving group.

Claims

1. A method for producing a polyalkylene glycol derivative having an amino group at an end, comprising the following [Step 1] to [Step 4]:

2. The method according to claim 1, wherein, in the [Step 3], the compound obtained in the [Step 2] of formula (VI) is reacted with the electrophile of formula (I) without performing purification of the compound of formula (VI).

3. The method according to claim 1, wherein, in the [Step 1], the compound of formula (IV) is reacted with the alkali metal or the alkali metal compound so that a ratio of the amounts of substances between the compound of formula (V) and the compound of formula (IV) is 100:

0 to 80;

20 after the compound of formula (V) is synthesized from the compound of formula (IV).

4. The method according to claim 1, wherein, in the [Step 1], a ratio of the amounts of substances between the compound of formula (V) and the compound of formula (IV) is set to 100:

0 to 98;

2 by distilling away the compound of formula (IV) under reduced pressure after the compound of formula (V) is synthesized from the compound of formula (IV).

5. The method according to claim 1, wherein the [Step 2] further comprises dissolving a reaction product obtained in the [Step 1] in the polymerization solvent.

6. The method according to claim 1, wherein the [Step 2] is performed at a reaction temperature in the range of 30 to 60°

C.

7. The method according to claim 1, wherein, in the [Step 3], an amount of the electrophile of formula (I) used is 1 to 20 equivalents relative to a number of moles of the compound of formula (VI).

8. The method according to claim 1, wherein the [Step 3] further comprises:

stopping reaction of the compound obtained in the [Step 2] of formula (VI) by an acid compound or a protic compound to obtain a compound of formula (IX); and

purifying the obtained compound of formula (IX), and

the reaction of the compound of formula (VI) with the electrophile of formula (I) in the [Step 3] is performed by an operation of reacting the purified compound of formula (IX) with the electrophile of formula (I) in the presence of a basic compound;

H—

(OR_A⁴)_n—

OR_A³ 

 

(IX)

wherein R_A³, R_A⁴, and n are as the same as defined in formulas (II) and (III).

9. The method according to claim 1, wherein a content of a heavy metal impurity in the reaction product comprising the compound of formula (III) obtained in the [Step 4] is 100 ppb or less, and the heavy metal impurity comprises one or more selected from the group consisting of Co, Ni, Pd, Pt, Rh, Ru, Cu, and Cr.

10. The method according to claim 1, wherein the [Step 4] further comprises:

reacting a reaction product comprising the compound of formula (III) with a basic compound to produce a salt after the compound of formula (III) is obtained, and thereafter removing the produced salt by filtration.

11. The method according to claim 1, wherein the [Step 4] further comprises:

reacting a reaction product comprising the compound of formula (III) with a basic compound to produce a salt after the compound of formula (III) is obtained, and thereafter removing the produced salt using an adsorption material.

12. The method according to claim 1, further comprising the following [Step 5] to [Step 8] after the [Step 3] or the [Step 4]:

[Step 5]

a step of reacting a product in the [Step 3] or the [Step 4] with a strong acid cation exchange resin and then washing the strong acid cation exchange resin to separate a substance other than the compound of formula (III);

[Step 6]

a step of reacting the strong acid cation exchange resin with a basic compound to separate the compound of formula (III);

[Step 7]

a step of concentrating a reaction liquid obtained in the [Step 6]; and

[Step 8]

a step of dripping a concentrated liquid obtained in the [Step 7] into a poor solvent for the compound of formula (III) to precipitate, thereby obtaining the compound of formula (III).

13. The method according to claim 1, wherein the [Step 2] further comprises:

confirming that the compound of formula (V) has been dissolved in the polymerization solvent before the reaction with the alkylene oxide, by checking that no cloudiness in the polymerization solvent is observed by visual observation.

14. The method according to claim 13, wherein a mass of the polymerization solvent is equal to or less than 10 times the mass of the compound of formula (V), in confirming that the compound of formula (V) has been dissolved in the polymerization solvent.

15. The method according to claim 1, wherein an area content ratio between a compound of formula (VII) and a compound of formula (VIII) in a reaction product comprising the compound of formula (III) obtained in the [Step 4] is 3% or less as measured by gel permeation chromatography, and a content ratio in terms of composition ratio of a compound of formula (IX) in the reaction product is 2 mol % or less as measured by proton nuclear magnetic resonance:

HNR_A²—

(OR_A⁴)_n—

OR_A³)₂ 

 

(VII)

NR_A²—

(OR_A⁴)_n—

OR_A³)₃ 

 

(VIII)

H—

(OR_A⁴)_n—

OR_A³ 

 

(IX)

wherein R_A², R_A³, R_A⁴, and n are the same as defined for formulas (I) to (III).

16. A method for producing a polyalkylene glycol derivative of formula (II), comprising the following [Step 1] to [Step 3]:

[Step 1]

a step of reacting a compound of formula (IV) with an alkali metal or an alkali metal compound selected from M, M⁺H⁻

, R_X⁻

M⁺, [R_Y]<sup>⋅

−</sup>

M⁺, and R_ZO⁻

M⁺ (wherein M represents an alkali metal, R_X represents an alkyl group having 1 to 20 carbon atoms, or an arylalkyl group having 7 to 20 carbon atoms, R_Y represents an aromatic compound that may have a substituent, and R_Z represents an alkyl group having 1 to 6 carbon atoms) to obtain a compound of formula (V);

R_A³O(R_A⁴O)_kH 

 

(IV)

wherein R_A³ represents a linear hydrocarbon group having 1 to 20 carbon atoms, or a branched or cyclic hydrocarbon group having 3 to 20 carbon atoms; and

R_A⁴ represents an alkylene group having 2 to 8 carbon atoms, and

k represents an integer of 2 to 5;

R_A³O(R_A⁴O)_k-1R_A⁴O⁻

M⁺ 

 

(V)

wherein R_A³, R_A⁴, and k are the same as defined in formula (IV); and

M is the same as defined for the alkali metal or the alkali metal compound;

[Step 2]

a step of reacting the compound of formula (V) with an alkylene oxide in a polymerization solvent to obtain a compound of formula (VI);

R_A³O(R_A⁴O)_n-1R_A⁴O⁻

M⁺ 

 

(VI)

where R_A³ and R_A⁴ are the same as defined in formula (IV);

M is the same as defined for the alkali metal or the alkali metal compound; and

n represents an integer of 3 to 450; and

[Step 3]

a step of reacting the compound of formula (VI) with an electrophile of formula (I-I-I) to obtain a compound of formula (II);