CN115959992A - Method for synthesizing polyethylene glycol monoacetic acid with single molecular weight - Google Patents
Method for synthesizing polyethylene glycol monoacetic acid with single molecular weight Download PDFInfo
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Abstract
The invention provides a method for synthesizing polyethylene glycol monoacetate with single molecular weight, which takes alcohol polymers with different polymerization degrees and tert-butyl bromoacetate as raw materials, carries out nucleophilic substitution reaction under the catalysis of alkali and a phase transfer catalyst to obtain polyethylene glycol mono-tert-butyl acetate, and then hydrolyzes to obtain polyethylene glycol monoacetate with single molecular weight; the conventional preparation process of the polyethylene glycol mono-tert-butyl acetate needs strong alkali for catalysis, the yield is low, and the reaction conditions are harsh; the method has mild reaction conditions and high yield, and simultaneously synthesizes a series of monoacetic acids with polyethylene glycol chains, thereby greatly expanding the range of substrates.
Description
Technical Field
The invention relates to the technical field of synthesis of polyethylene glycol derivatives, in particular to a synthesis method of polyethylene glycol monoacetic acid with single molecular weight.
Background
Polyethylene glycol (PEG) has good biocompatibility, and introduction of PEG fragments into the medicine can reduce immunoreaction, and increase stability, solubility and passive targeting of the medicine. The single-molecule PEG chain is often used as a linking group (linker) of a protein degradation targeting chimera (PROTAC) medicament, the structure has low toxicity and high compatibility with human tissues, the metabolism time is prolonged, and the effect of medicament effect is improved, and the PEG modification of the medicament gradually becomes a key means for novel efficient medicament synthesis development.
The tert-butyl acetate is a raw material or a key intermediate for preparing a plurality of medicines, is also an excellent solvent of nitrocellulose and a shockproof additive of gasoline, and has wide application in the fields of medicine, chemical industry and the like. The conventional preparation method is generally to synthesize acetyl chloride or acetic anhydride and tert-butyl alcohol under the action of zinc chloride, however, the tert-butyl alcohol has larger steric hindrance and lower yield of synthesized products. The prior synthesis method of the polyethylene glycol mono-tert-butyl acetate has less published documents, and the hydrolyzed polyethylene glycol mono-acetic acid can be directly used as a drug intermediate, so the method has excellent application prospect.
The patent with publication number CN113387802A discloses a synthesis method of propionic acid-polyethylene glycol-tert-butyl propionate, which has long reaction time and still lower yield; the synthesis method of PEG-modified poly (ethylene glycol) mono (tert-butyl) acetate is less common, and the price of poly (ethylene glycol) mono (tert-butyl) acetate is extremely high due to factors such as large raw material demand, low yield, environmental pollution caused by byproducts and the like.
Disclosure of Invention
In view of the above, the invention provides a synthesis method of single molecular weight PEG monoacetic acid, which adopts PEG alcohol as potassium alcoholate to carry out nucleophilic substitution under the action of alkali and a phase transfer catalyst, and has mild conditions and high yield of target products.
The technical scheme of the invention is realized as follows: the invention provides a synthesis method of single molecular weight PEG monoacetic acid, which comprises the following steps:
s1, taking a compound A and tert-butyl bromoacetate as reaction raw materials, and reacting under the catalysis of alkali and a phase transfer catalyst to obtain a compound B, wherein the alkali comprises one of potassium hydroxide, sodium hydride, potassium tert-butoxide, metallic sodium or inorganic alkali;
and S2, adding acid into the compound B obtained in the step S1 for hydrolysis, and obtaining the polyethylene glycol monoacetic acid with the molecular weight after complete reaction.
On the basis of the above technical solution, preferably, the molecular formula of the mono-molecular weight polyethylene glycol monoacetate is:
wherein n =0, 1, 2, 3 or 7,R is->
One of them.
On the basis of the above technical scheme, preferably, the compound A is
Wherein n =0, 1, 2, 3 or 7,R is->
One of them.
Preferably, R is
In the general molecular formula of mono-molecular polyethylene glycol monoacetate is->
Still more preferably, the base in step S1 is potassium hydroxide.
In the specific synthesis method, the step S1 further includes the following steps:
s1-1, dissolving a compound A in dichloromethane, adding alkali and a phase transfer catalyst, and stirring for 0.5-1h at the temperature of 20-25 ℃;
s1-2, dropwise adding tert-butyl bromoacetate, continuing to react for 2-4h, monitoring by TLC after the reaction is completed, adding water and dichloromethane, stirring for 0.5-1h, extracting, and concentrating an organic phase to obtain a compound B;
preferably, in the specific synthesis method, the step S2 further comprises the following steps:
s2-1, dissolving the compound B obtained in the step S1 in methanol, dropwise adding acid liquor, and stirring at 20-25 ℃ for 12-16h;
s2-2, after the TLC monitoring reaction is completed, adding water and dichloromethane, stirring for 0.5-1h, extracting, and concentrating an organic phase to obtain the polyethylene glycol monoacetate.
Preferably, the molar ratio of compound a, base, phase transfer catalyst and tert-butyl bromoacetate in step S1-1 is 1: (1.2-2): (0.02-0.04): (1.2-2).
Preferably, the phase transfer catalyst in step S1-1 includes one of tetrabutylammonium chloride (TBAC), tetrabutylammonium fluoride, tetrabutylammonium hydroxide or tetrabutylammonium perchlorate.
Preferably, the developing solvent for TLC monitoring comprises dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (12-10): 1.
preferably, the acid solution in step S2-1 comprises hydrochloric acid or nitric acid, and the molar concentration of the acid solution is 2.5-4M.
Preferably, the volume ratio of water to dichloromethane in step S2-2 is 1: (1-1.5).
Compared with the prior art, the synthesis method of the PEG monoacetic acid with the single molecular weight has the following beneficial effects:
(1) In the existing synthesis method of single molecular weight PEG mono-tert-butyl acetate, the raw materials are reacted by strong alkali such as sodium hydride or potassium tert-butoxide, so the required conditions are harsh and the yield is low; in the invention, potassium hydroxide is used as alkali, PEG alcohol is used as potassium alkoxide, nucleophilic substitution reaction is carried out on the potassium alkoxide and bromine to synthesize PEG mono-tert-butyl acetate, and then single molecular weight PEG mono-acetic acid is obtained by acid hydrolysis, the condition is mild, and the product yield is high;
(2) In the conventional synthesis reaction of tert-butyl acetate, potassium tert-butoxide has large steric hindrance and can hinder the reaction from proceeding; the TBAC is used as a phase transfer catalyst to catalyze the dissolution of potassium alcoholate, so that the nucleophilic substitution reaction efficiency is effectively improved;
(3) The existing synthesis methods of single molecular weight PEG tert-butyl monoacetate and monoacetic acid are few, and the long PEG chain tert-butyl acetate is rare. The invention prolongs the range of the PEG chain of the monoacetic acid, effectively expands the application range of the product, directly plays a role as a drug intermediate and has good market prospect and economic benefit.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments of the present invention, belong to the protection scope of the present invention.
Example 1
A method for synthesizing mono-molecular weight polyethylene glycol monoacetic acid comprises the following steps:
s1, dissolving A1 (100g, 0.68mol) in 500mLDCM, adding solid KOH (76.1g, 1.36mol) and TBAC (5 g), stirring at 20 ℃ for 0.5h, dropwise adding tert-butyl bromoacetate (262g, 1.36mol), continuing to react for 2h, performing TLC (DCM: meOH = 12) spotting to show that the raw materials are completely reacted, adding 500mL of water and 500mLDCM, stirring for 0.5h, demixing, washing an organic phase for 2 times by using 200mL of saturated NaCl aqueous solution, drying the organic phase, and performing spin drying to obtain 150g of white oily matter with the yield of 85%;
s2, dissolving B1 (150g, 0.57mol) in 500 mM LEH, dropwise adding 1mL of 2.5M hydrochloric acid, stirring at 20 ℃ for 12h, performing TLC (DCM: meOH = 12).
Of D1 1 HNMR was (400MHz, chloroform-d) Δ 4.00 (s, 2H), 3.72 (dd, J =4.4,1.5
Hz,2H),3.70–3.61(m,2H),1.47(s,9H)。
The above method is applicable to different PEG chain lengths.
Examples 2 to 3
A method for synthesizing mono-molecular weight polyethylene glycol monoacetic acid, which is different from the method in example 1 in that n =2, 3 and the phase transfer catalyst is tetrabutyl ammonium hydroxide.
The yield of the desired product D2 in example 2 was 93%, the preparation of D2 1 HNMR is (400MHz, chloroform-d) delta 3.97 (s, 2H), 3.72-3.63 (m, 6H), 3.58 (s, 2H), 1.43 (s, 9H).
The yield of the target product D3 in example 3 was 91%, the production of D3 1 HNMR was (400MHz, chloroform-d) delta 4.00 (s, 2H), 3.74-3.63 (m, 10H), 3.62-3.57 (m, 2H), 1.46 (s, 9H).
Example 4
A method for synthesizing polyethylene glycol monoacetate with single molecular weight comprises the following steps:
s1, dissolving A4 (100g, 0.69mol) in 500mL DCM, adding solid KOH (46.45g, 0.83mol) and TBAC (7.6 g), stirring for 1h at 25 ℃, dropwise adding tert-butyl bromoacetate (161.89g, 0.83mol), continuing the reaction for 4h, TLC (DCM: meOH = 10) spotting the plate shows the raw materials are completely reacted, adding 500mL of water and 500mL DCM, stirring for 1h, layering, washing the organic phase with 200mL of saturated NaCl aqueous solution for 2 times, drying the organic phase, and spin-drying to obtain 158g of white oil B4 with yield of 89%;
s2, dissolving B4 (158g, 0.61mol) in 500 mM LEOH, dropwise adding 1mL of 4M hydrochloric acid, stirring at 25 ℃ for 169h, performing TLC (DCM: meOH = 10).
Of D4 1 HNMR was (400MHz, chloroform-d) Δ 4.00 (s, 2H), 3.72 (dd, J =4.4,1.5
Hz,2H),3.70–3.61(m,2H),1.47(s,9H)。
Examples 5 to 6
A method for synthesizing polyethylene glycol monoacetate, which is different from example 4 in that n =3,7 and the phase transfer catalyst is tetrabutylammonium fluoride.
Example 5 yield of the desired product D5 was 88%, of D6 1 H NMR(400MHz,Chloroform-d)δ4.15(s,2H),3.76–3.71(m,2H),3.70–3.60(m,28H),3.38(dd,J＝5.6,4.5Hz,2H)。
The yield of the desired product D6 in example 6 was 85%, the preparation of D6 1 H NMR(400MHz,Chloroform-d)δ4.15(s,2H),3.74(ddd,J＝5.5,3.3,1.1Hz,2H),3.71–3.59(m,28H),3.58–3.51(m,2H),3.37(s,3H)。
Example 7
A method for synthesizing mono-molecular weight polyethylene glycol monoacetic acid comprises the following steps:
s1, dissolving A7 (100g, 0.21mol) in 500mL of CCM, adding solid KOH (23.52g, 0.42mol) and TBAC (4.7 g), stirring at 24 ℃ for 0.8h, dropwise adding tert-butyl bromoacetate (81.92g, 0.42mol), continuing to react for 3h, performing TLC (DCM: meOH = 11) to ensure that the raw materials are completely reacted, adding 500mL of water and 500mL of CCM, stirring for 0.8h, demixing, washing an organic phase with 200mL of saturated aqueous NaCl solution for 2 times, drying the organic phase, and spin-drying to obtain 102g of white oily B7 with the yield of 83%;
s2, B7 (102g, 0.17mol) was dissolved in 500mL MeOH, 1mL of 3M hydrochloric acid was added dropwise, stirred at 24 ℃ for 14h, tlc (DCM: meOH = 11) spot plate showed complete reaction of the starting materials, 500mL of water and 500mL of dccm were added, stirred for 0.8h, the layers were separated, the organic phase was washed 2 times with 200mL of saturated aqueous NaCl solution, the organic phase was dried and spin dried to give crude, silica gel column purified to give 79g of D7 as a white oil in 88% yield.
Comparative examples 1 to 2
The difference between the synthesis method of the polyethylene glycol monoacetate and the synthesis method of the polyethylene glycol monoacetate in the embodiment 7 is that the alkali is sodium metal and potassium tert-butoxide.
The yield of the target product D1 in comparative example 1 is 63%, and the yield of the target product D1 in comparative example 2 is 59%.
Therefore, the synthetic route of the invention is suitable for n =0, 1, 2, 3 or 7, and the yield is high and is more than 85%.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.
Claims (10)
1. A method for synthesizing polyethylene glycol monoacetate with single molecular weight is characterized by comprising the following steps:
s1, taking a compound A and tert-butyl bromoacetate as reaction raw materials, and reacting under the catalysis of alkali and a phase transfer catalyst to obtain a compound B, wherein the alkali comprises one of potassium hydroxide, sodium hydride, potassium tert-butoxide, metallic sodium or inorganic alkali;
and S2, adding acid into the compound B obtained in the step S1 for hydrolysis, and obtaining the mono-molecular weight polyethylene glycol mono-tert-butyl acetate after complete reaction.
2. The method of synthesizing polyethylene glycol monoacetate according to claim 1, wherein the polyethylene glycol monoacetate has a molecular formula:
wherein n =0, 1, 2, 3 or 7,R is +>
One of them.
3. The method of synthesizing polyethylene glycol monoacetate according to claim 1, wherein the compound A is
Wherein n =0, 1, 2, 3 or 7,R is->
One of them.
4. The method for synthesizing polyethylene glycol monoacetate of monomolecular weight according to claim 3, wherein R is
When the molecular general formula of the mono-molecular polyethylene glycol mono-acetic acid is shown in the specification
5. The method for synthesizing polyethylene glycol monoacetate of monomolecular weight according to claim 1, wherein the alkali in step S1 is potassium hydroxide.
6. The method for synthesizing polyethylene glycol monoacetate according to claim 1, wherein the step S1 further comprises the following steps:
s1-1, dissolving a compound A in dichloromethane, adding alkali and a phase transfer catalyst, and stirring for 0.5-1h at the temperature of 20-25 ℃;
s1-2, dropwise adding tert-butyl bromoacetate, continuing to react for 2-4h, monitoring by TLC to complete the reaction, adding water and dichloromethane, stirring for 0.5-1h, extracting, and concentrating an organic phase to obtain a compound B.
7. The method for synthesizing polyethylene glycol monoacetate according to claim 1, wherein the step S2 further comprises the following steps:
s2-1, dissolving the compound B obtained in the step S1 in methanol, dropwise adding acid liquor, and stirring at 20-25 ℃ for 12-16h;
and S2-2, after the TLC monitoring reaction is completed, adding water and dichloromethane, stirring for 0.5-1h, extracting, and concentrating an organic phase to obtain the mono-molecular weight polyethylene glycol monoacetate.
8. The method for synthesizing polyethylene glycol monoacetate according to claim 6, wherein the molar ratio of the compound A, the alkali, the phase transfer catalyst and the tert-butyl bromoacetate in the step S1-1 is 1: (1.2-2): (0.02-0.04): (1.2-2).
9. The method for synthesizing polyethylene glycol monoacetate of claim 6, wherein the phase transfer catalyst in step S1-1 comprises one of tetrabutylammonium chloride (TBAC), tetrabutylammonium fluoride, tetrabutylammonium hydroxide or tetrabutylammonium perchlorate.
10. The method for synthesizing polyethylene glycol monoacetate according to any one of claims 6 to 7, wherein the developing solvent monitored by TLC comprises dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is (12-10): 1.
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