Preparation method of [2-[2-(dibenzylamino) ethyoxyl] ethyoxyl] acetic acid-13C

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a preparation method of [2-[2-(dibenzylamino) ethyoxyl] ethyoxyl] acetic acid-13C. Comprising the following steps: step 1, synthesizing [2-[2-(dibenzylamino) ethyoxyl] ethyoxyl] acetonitrile-13C by taking p-cyanobenzene sulfonate, p-cyanobenzene sulfonate or p-iodobenzene sulfonate as raw materials; step 2, reacting [2-[2-(dibenzylamino) ethyoxyl] ethyoxyl] acetonitrile-13C with acid, and washing to obtain [2-[2-(dibenzylamino) ethyoxyl] ethyoxyl]; acetic acid-13C; the method has the advantages of mild reaction conditions, simple reaction device, convenience in operation, convenience in product purification and high yield.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 Preparation method of C. Background Art

[0002] The description of the background technology in the present invention belongs to the related technology related to the present invention, which is only used to illustrate and facilitate the understanding of the invention content of the present invention, and should not be understood as the applicant explicitly believes or inferred that the applicant believes that it is the prior art of the present invention on the filing date of the first application.

[0003] [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetic acid is an important pharmaceutical intermediate and organic chemical raw material. It is widely used in the treatment of AIDS, diabetes and other industries. The fourth-generation anti-HIV drug gp41 variant peptide has the characteristics of high activity and long action time in inhibiting human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). It can effectively reduce the susceptibility to degradation by peptidases or proteases in the body and minimize the need for continuous administration. [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetic acid is a key intermediate for the preparation of the fourth-generation anti-HIV drug gp41 variant peptide. Semaglutide is a very effective GLP-1 analogue for the treatment of obese diabetes. It has strong hydrophilicity and can not only bind very tightly to albumin, thereby masking the hydrolysis site of dipeptidyl peptidase 4 (DPP-4), but also effectively reduce renal excretion, prolong the biological half-life, and make the long circulation effect significant. [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid is an important pharmaceutical intermediate for the preparation of semaglutide. There are many methods for synthesizing analogs of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid. Maciej Adamczyk reported earlier on the synthesis of similar compounds. Diethylene glycol amine was used as the starting material, and the amino group was protected by Boc or Cbz. It was reacted with tert-butyl bromoacetate or ethyl bromoacetate under the action of bases such as sodium hydrogen sulfide or potassium tert-butoxide. The amino atom of the monoprotected diethylene glycol amine was further activated by the base and continued to react with tert-butyl bromoacetate or ethyl bromoacetate, resulting in low reaction yield and difficulty in purification. Gao Yong reported in Chemical Reagents in 2006 that triethylene glycol was used as the starting material, chlorinated, and then reacted with potassium phthalimide, then oxidized to the carboxyl group, and then deprotected to obtain the product. This route has the disadvantages of low yield and expensive synthetic raw materials. The yield of this route for the synthesis of 8-amino-3,6-dioxa-octanoic acid is very low and is completely unsuitable for mass production. CN201310617149.X uses benzaldehyde and diglycolamine to react to obtain imine to protect the nitrogen atom, and then reacts with tert-butyl bromoacetate to form ether, and then stirs in acid water overnight to obtain the desired product. However, the reaction yield is not high, and the reaction requires a large amount of toluene, which has a great impact on the environment. [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C It has great application prospects in medicine and biology in metabolic tracing, but the current synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 C has not been reported.

[0004] The existing methods for synthesizing analogs of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid mainly include:

[0005] 1. Maciej Adamczyk reported earlier on the synthesis of a similar compound, using diglycolamine as the starting material, using Boc or Cbz to protect the amino group, and reacting with tert-butyl bromoacetate or ethyl bromoacetate under the action of a base such as sodium hydrogen sulfide or potassium tert-butoxide. The amino atom of the mono-protected diglycolamine will be further activated by the base and continue to react with tert-butyl bromoacetate or ethyl bromoacetate, resulting in a low reaction yield and difficulty in purification.

[0006] 2. Gao Yong reported in Chemical Reagents in 2006 that triethylene glycol was used as the starting material, which was then chlorinated and reacted with potassium phthalimide, then oxidized to the carboxyl group, and then deprotected to obtain the product. This route has the disadvantages of low yield and expensive synthetic raw materials. The yield of this route for synthesizing 8-amino-3,6-dioxanoic acid is very low and is completely unsuitable for mass production.

[0007] 3. CN201310617149.X uses benzaldehyde and diglycolamine to react to obtain imine to protect the nitrogen atom, and then reacts with tert-butyl bromoacetate to form ether, and then stirs in acid water overnight to obtain the desired product. However, the reaction yield is not high, and the reaction requires a large amount of toluene, which has a great impact on the environment. Summary of the invention

[0008] The purpose of the embodiment of the present invention is to provide a [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 The invention discloses a preparation method of C. The synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid by this route has not been reported in the literature. The reaction raw materials are not volatile, easy to obtain and easy to chemically synthesize. The reaction conditions are mild. The reaction device is simple and easy to operate. The product is easy to purify and has a high yield. The invention fills the blank of the synthesis of isotope-labeled [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid in China.

[0009] A [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 The preparation method of C comprises the following steps:

[0010] Step 1: Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- using p-bromocyanomethylbenzenesulfonate, p-chlorocyanomethylbenzenesulfonate or p-iodocyanomethylbenzenesulfonate as raw materials 13 C:

[0011] Step 2: [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C reacts with an acid and then washes to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C;

[0012]

[0013] Further, the following steps are included:

[0014] 100ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 413mg, 1.1eq), tetrahydrofuran (10ml), replace with nitrogen, add 60% sodium hydrogen sulfide (64mg, 1.2eq) at 10℃, purge with nitrogen, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate- 13 C (SM-0, 277 mg, 1.0 eq) and tetrahydrofuran (10 ml) were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the mixture was collected and dried to obtain the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (300 mg, colorless liquid);

[0015] 100ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (300 mg, 1.0 eq), HCl (10 ml) nitrogen purging, heated to 100 ° C for 18 h, extracted with DCM three times, washed once with saturated brine, dried with sodium sulfate, passed through a column, collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid-13C (270 mg, colorless liquid).

[0016] Further, the following steps are included:

[0017] 100ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 1.24g, 1.1eq), tetrahydrofuran (20ml), nitrogen replacement, add 60% sodium hydrogen sulfide (208mg, 1.3eq) at 10℃, nitrogen purge, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate- 13 C (SM-0, 846 mg, 1.0 eq) and tetrahydrofuran (20 ml) were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (930 mg, colorless liquid);

[0018] 100ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13C (938 mg, 1.0 eq), HCl (25 ml) nitrogen purging, heated to 100 ° C for 18 h. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, and collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C (880 mg, colorless liquid).

[0019] Furthermore, step 1 includes the following steps:

[0020] 300ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 2.5g, 1.1eq), tetrahydrofuran (10ml), nitrogen replacement, add 60% sodium hydrogen sulfide (448mg, 1.4eq) at 10℃, nitrogen purge, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate- 13 C (SM-0, 277 mg, 1.0 eq) and tetrahydrofuran (10 ml) were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the mixture was collected and dried to obtain the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (1.85 g, colorless liquid);

[0021] 100ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (1.85 g, 1.0 eq), HCl (10 ml) nitrogen purging, heated to 100 ° C for 18 h. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, and collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C (1.7 g, colorless liquid).

[0022] The embodiments of the present invention have the following beneficial effects:

[0023] The synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid by this route has not been reported in the literature. The reaction raw materials are not volatile, easy to obtain and easy to chemically synthesize. The reaction conditions are mild. The reaction device is simple and easy to operate. The product is easy to purify and has a high yield. This fills the gap in the synthesis of isotope-labeled [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid in China.

[0024] The present invention avoids using complex or difficult-to-obtain labeling compounds as starting materials and directly uses commercially available labeled potassium cyanide- 13 C as the starting material (barium carbonate- 13 C Synthesis of Potassium Cyanide 13C, the synthesis is very simple) to achieve p-bromocyanomethylbenzenesulfonate- 13 C, [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 The synthesis process of C is simplified;

[0025] The [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid synthesized by the present invention 13 C can not only fill the domestic gap, but also help meet the huge needs of the domestic and international markets;

[0026] The reaction conditions of the present invention are mild, the reaction device is simple, and a high yield of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C, can be widely used in medicine, and biological marker metabolism. DETAILED DESCRIPTION

[0027] The present application is further described below in conjunction with embodiments.

[0028] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, in the following description, different "one embodiment" or "embodiment" does not necessarily refer to the same embodiment. Different embodiments can be replaced or combined, and for ordinary technicians in this field, other implementation methods can be obtained based on these embodiments without creative work.

[0029] A [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 The preparation method of C comprises the following steps:

[0030] Step 1: Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- using p-bromocyanomethylbenzenesulfonate, p-chlorocyanomethylbenzenesulfonate or p-iodocyanomethylbenzenesulfonate as raw materials 13 C:

[0031] Step 2: [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C reacts with an acid and then washes to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C;

[0032]

[0033] Example 1

[0034] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13C: 100ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 413mg, 1.1eq), tetrahydrofuran (10ml), replace with nitrogen, add 60% sodium hydrogen (64mg, 1.2eq) at 10℃, purge with nitrogen, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate-13C (SM-0, 277mg, 1.0eq) and tetrahydrofuran (10ml), react at room temperature for 15h. After the reaction, add water to quench the reaction, extract with ethyl acetate 3 times, wash the organic phase with saturated brine once, dry with sodium sulfate, pass through a column, collect and spin dry to obtain the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (300 mg, colorless liquid).

[0035] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 C(IM-2): 100 ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (300 mg, 1.0 eq), HCl (10 ml) nitrogen purging, heated to 100 ° C for 18 h. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, and collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C (270 mg, colorless liquid).

[0036] Example 2

[0037] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C: 100ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 1.24g, 1.1eq), tetrahydrofuran (20ml), replace with nitrogen, add 60% sodium hydrogen sulfide (208mg, 1.3eq) at 10℃, purge with nitrogen, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate- 13 C (SM-0, 846 mg, 1.0 eq) and tetrahydrofuran (20 ml) were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (930 mg, colorless liquid).

[0038] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 C(IM-2): 100 ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile-13 C (938 mg, 1.0 eq), HCl (25 ml) nitrogen purging, heated to 100 ° C for 18 h. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, and collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C (880 mg, colorless liquid).

[0039] Example 3

[0040] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C: 300ml single-necked flask, three-way, add 2-(2-benzyl)diglycolamine (SM-1, 2.5g, 1.1eq), tetrahydrofuran (10ml), replace with nitrogen, add 60% sodium hydrogen sulfide (448mg, 1.4eq) at 10℃, purge with nitrogen, react at room temperature for 1h, add p-bromocyanomethylbenzenesulfonate- 13 C (SM-0, 277 mg, 1.0 eq) and tetrahydrofuran (10 ml) were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (1.85 g, colorless liquid).

[0041] Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 C(IM-2): 100 ml single-necked flask, connected with condenser and three-way connection, add [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C (1.85 g, 1.0 eq), HCl (10 ml) nitrogen purging, heated to 100 ° C for 18 h. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, and collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C (1.7 g, colorless liquid).

[0042] It should be noted that:

[0043] In addition to p-bromocyanomethylbenzenesulfonate, p-chlorocyanomethylbenzenesulfonate and p-iodocyanomethylbenzenesulfonate can also be used as the raw material for the first step.

[0044] In addition to hydrochloric acid, other acids (such as sulfuric acid) and other bases (such as sodium hydroxide) can also be used in the second step reaction.

[0045] The present invention is also applicable to the isotope-labeled synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 14Synthesis of C.

[0046] It should be noted that the above embodiments can be freely combined as needed. The above description is only the preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention can have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid 13 The preparation method of C is characterized in that The steps include: Step 1: Synthesis of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- using p-bromocyanomethylbenzenesulfonate, p-chlorocyanomethylbenzenesulfonate or p-iodocyanomethylbenzenesulfonate as raw materials 13 C: Step 2: [2-[2-(Dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C reacts with an acid and then washes to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C; 2. The [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid according to claim 1 13 The preparation method of C is characterized in that The steps include: 100ml single-necked flask, three-way, add SM-1, 413mg, 1.1eq of 2-(2-benzyl)diglycolamine, 10ml tetrahydrofuran, nitrogen replacement, add 64mg, 1.2eq, 60% mass fraction sodium hydrogen at 10℃, nitrogen purging, react at room temperature for 1h, add SM-0, 277mg, 1.0eq of p-bromocyanomethylbenzenesulfonate- 13 C and 10 ml of tetrahydrofuran were reacted at room temperature for 15 h. After the reaction, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the mixture was collected and dried to obtain the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C300mg, colorless liquid; A 100 ml single-necked flask was connected to a condenser and a three-way connection. 300 mg and 1.0 eq of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile were added. 13 C, 10 ml of HCl nitrogen purge, heated to 100 ° C for 18 hours. DCM was added for extraction 3 times, saturated brine was washed once, dried with sodium sulfate, passed through a column, and the mixture was collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C270mg, colorless liquid.

3. The [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid according to claim 1 13 The preparation method of C is characterized in that The steps include: A 100 ml single-mouth flask with a three-way connection was added with SM-1, 1.24 g, 1.1 eq of 2-(2-benzyl)diglycolamine, 20 ml of tetrahydrofuran, and nitrogen replacement. At 10°C, 208 mg, 1.3 eq of sodium hydrogen with a mass fraction of 60% was added, nitrogen was purged, and the reaction was carried out at room temperature for 1 hour. SM-0, 846 mg, 1.0 eq of p-bromocyanomethylbenzenesulfonate-13C and 20 ml of tetrahydrofuran were added dropwise, and the reaction was carried out at room temperature for 15 hours. After the reaction was completed, water was added to quench the reaction, and the organic phase was extracted with ethyl acetate three times. The organic phase was washed with saturated brine once, dried with sodium sulfate, passed through a column, and the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C930mg, colorless liquid; A 100 ml single-necked flask was connected to a condenser and a three-way connection, and 938 mg, 1.0 eq of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C, 25 ml of HCl nitrogen purge, heated to 100 ° C for 18 hours. DCM was added for extraction 3 times, washed once with saturated brine, dried with sodium sulfate, passed through a column, collected and dried to obtain 880 mg of colorless liquid [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C.

4. [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid according to claim 1 13 The preparation method of C is characterized in that Step 1 includes the following steps: 300ml single-necked flask, three-way, add SM-1, 2.5g, 1.1eq of 2-(2-benzyl)diglycolamine, 10ml of tetrahydrofuran, nitrogen replacement, add 448mg, 1.4eq of 60% sodium hydrogen at 10℃, nitrogen purging, react at room temperature for 1h, add SM-0, 277mg, 1.0eq of p-bromocyanomethylbenzenesulfonate- 13 C and 10 ml of tetrahydrofuran, react at room temperature for 15 h; after the reaction, add water to quench the reaction, extract with ethyl acetate three times, wash the organic phase with saturated brine once, dry with sodium sulfate, pass through a column, collect and spin-dry to obtain the compound [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile- 13 C 1.85g, colorless liquid; A 100 ml single-necked flask was connected to a condenser and a three-way connection. 1.85 g, 1.0 eq of [2-[2-(dibenzylamino)ethoxy]ethoxy]acetonitrile was added. 13 C, 10 ml of HCl nitrogen purge, heated to 100 ° C for 18 hours. DCM was added for extraction 3 times, saturated brine was washed once, dried with sodium sulfate, passed through a column, and the mixture was collected and dried to obtain [2-[2-(dibenzylamino)ethoxy]ethoxy]acetic acid- 13 C1.7g, colorless liquid.

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