CN113620869B

CN113620869B - Preparation method of betrixaban

Info

Publication number: CN113620869B
Application number: CN202010374914.XA
Authority: CN
Inventors: 冯玉杰; 叶四明; 庞正伟; 曹玉婷; 范利星
Original assignee: JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
Current assignee: JIANGXI SYNERGY PHARMACEUTICAL CO Ltd
Priority date: 2020-05-06
Filing date: 2020-05-06
Publication date: 2023-04-18
Anticipated expiration: 2040-05-06
Also published as: CN113620869A

Abstract

The invention provides a preparation method of betrixaban, which comprises the steps of reacting a compound shown in a structural formula II or a salt thereof with MN (CH) in liquid dimethylamine ₃ ) ₂ Reacting the dimethylamine solution to obtain the shellfish with the structural formula I(iii) troxiban; wherein M = Li or MgX; wherein, X is selected from one of Cl, br and I. The preparation method has high yield and high product purity, can basically avoid the generation of the monoammonium impurity and the dechlorination impurity, and greatly simplifies the subsequent refining process. In addition, the preparation method has single solvent, avoids the use of mixed solvent, is convenient for recycling the solvent in the later period, and can reduce the amount of three wastes.

Description

Preparation method of betrixaban

Technical Field

The invention belongs to the field of organic chemistry, and particularly relates to a preparation method of betrixaban.

Background

Betrixaban (Betrixaban), chemical name: n- (5-chloro-2-pyridinyl) -2- [ [4- [ (dimethylamino) iminomethyl ] benzoyl ] amino ] -5-methoxybenzamide, CAS number: 330942-05-7. The structural formula is shown as I.

The betrixaban is first approved to be listed in the market in 6 months in 2017, is the 4 th direct factor Xa inhibitor anticoagulant in the global market after rivaroxaban, apixaban and edoxaban, and is subjected to FDA priority evaluation. Betrixaban is used clinically to prevent venous thromboembolism in hospitalized patients with acute medical conditions at risk for thromboembolic complications due to moderate or severe activity limitation and other thromboembolic risk factors.

CN101595092B (published 2009, 12 months and 2 days) discloses a preparation method of betrixaban, namely: using 5-methoxy-2-nitrobenzoic acid (compound of structural formula VI) and 2-amino-5-chloropyridine (compound of structural formula VII) as starting materials in POCl ₃ Reacting with pyridine in the presence of pyridine to obtain a compound with a structural formula V;

reducing the compound with the structural formula V by palladium-carbon to obtain a compound with a structural formula IV;

carrying out amidation reaction on the compound with the structural formula IV and p-cyanobenzoyl chloride (a compound with a structural formula III) to obtain a compound with a structural formula II;

finally reacting the compound of formula II with lithium dimethylamide in an aprotic solvent (such as tetrahydrofuran, diethyl ether, dimethoxymethane, dioxane, hexane, methyl tert-butyl ether, heptane, cyclohexane and mixtures thereof, with tetrahydrofuran being particularly preferred) via a nucleophilic addition reaction to give betrixaban of formula I:

wherein, the compound of the structural formula II is prepared into the betrixaban of the structural formula I, the yield is 76.7%, the HPLC purity is 98%, and the obtained betrixaban contains 1.14% of dechlorinated impurities (the compound of the structural formula VIII) and more than 0.1% of monomethyl impurities (the compound of the structural formula IX). The monomethyl impurity is believed to be generated during the formation of the amidino intermediate. The structures of these two impurities are similar to that of betrixaban and are difficult to remove by a refining process, thus seriously affecting product quality and yield.

In view of the above insufficiency, publication No. CN102762538B (publication No. 2012, 10, 31) proposes another preparation method. The method is the most different from the method disclosed in the above CN101595092B chinese patent application in that: firstly, synthesizing a compound A containing dimethyl amidino, and then reacting the compound A with a compound with a structural formula IV to obtain betrixaban; the synthetic route is as follows:

the patent document discloses two methods for preparing the compound A, namely a method 2, which has high requirements on equipment and serious environmental pollution and is difficult to implement industrial production due to the use and treatment of a large amount of highly corrosive hydrogen chloride gas. And in the process of hydrolyzing the compound G-1 or the compound G-2 by an aqueous solution or an alcoholic solution of a base to obtain the compound A, the dimethyl amidine group is easily hydrolyzed to an amide group, resulting in a new amide impurity. In addition, the compound A has high polarity and good water solubility, so that the yield of the compound A is low; the experiment shows that the yield of the compound A obtained by the hydrolysis reaction in the step is only 50 percent. In addition, the condensation reaction of the last step uses an expensive condensing agent, and the condensing agent is converted into waste after the reaction is finished, so that the pollution is high, and the cost is high.

In summary, there is currently no process particularly suitable for the industrial production of betrixaban.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a preparation method of betrixaban. The method has high yield, high product purity, and low total impurity content, and can control dechlorination impurity and monomethyl impurity below 0.10%.

In order to achieve the technical effects, the invention adopts the following technical scheme:

a process for preparing betrixaban comprises reacting a compound of formula II or a salt thereof with MN (CH) in a liquid dimethylamine ₃ ) ₂ Reacting the dimethylamine solution to obtain the betrixaban with a structural formula I;

wherein M = Li or MgX; wherein, X is selected from one of Cl, br and I.

Preferably, the MN (CH) ₃ ) ₂ The preparation method comprises the following steps:

under the protection of nitrogen, liquid dimethylamine and one selected from n-butyl lithium, tert-butyl lithium, hexyl lithium, n-propyl magnesium chloride, isopropyl magnesium chloride, cyclohexyl magnesium chloride, phenyl magnesium chloride, benzyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide, isobutyl magnesium bromide, n-pentyl magnesium bromide, cyclopentyl magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl magnesium bromide, 4-diphenyl magnesium bromide, 4-phenoxyphenyl magnesium bromide, 4-fluorophenyl magnesium bromide, 4-chlorophenyl magnesium bromide and methyl magnesium iodide are reacted at the temperature of below 0 ℃ to prepare MN (CH) ₃ ) ₂ 。

More preferably, the MN (CH) ₃ ) ₂ The preparation method comprises the following steps:

under the protection of nitrogen, liquid dimethylamine reacts with one of n-butyl lithium, tert-butyl lithium, hexyl lithium, isopropyl magnesium chloride, isopropyl magnesium bromide and n-amyl magnesium bromide at the temperature of below 0 ℃.

Preferably, the compound of formula II or salt thereof is reacted with MN (CH) ₃ ) ₂ The molar ratio of (b) is 1: 1 to 1: 10, more preferably 1:2 to 1: 7.

Preferably, the temperature of the reaction is ≦ 5 deg.C, more preferably ≦ 0 deg.C.

The compounds of formula II, or salts thereof, may be prepared by methods known in the art, for example using the method described in CN101595092B, starting from 5-methoxy-2-nitrobenzoic acid and 2-amino-5-chloropyridine.

According to the method for preparing the betrixaban, the reaction molar yield is more than 90%, the purity of the betrixaban prepared by HPLC detection is more than 99.5%, the dechlorination impurity (the compound of the structural formula VIII) is less than 0.10%, the monomethylamine impurity (the compound of the structural formula IX) is less than 0.10%, and the contents of the two impurities are below the limit required by the ICH guiding principle.

Compared with the prior art, the preparation method provided by the invention has remarkable improvements in product quality and product yield. Table 1 shows a comparison of the process of the present invention and the prior art in terms of yield, purity and impurity content of betrixaban according to the teachings of the prior art CN101595092B and CN 102762538B.

Table 1 comparison of the process of the invention with the prior art

	CN101595092B	CN102762538B	Method of the invention
				Yield of betrixaban ^a	76.7％	79.9％	＞90％
HPLC purity	98％	＞99.3％	＞99.5％
				Dechlorinated impurities	1.14％	0.083％	＜0.10％
Monomethylamine impurities	＞0.1％	Is unknown	＜0.10％

^a : the yield refers only to the yield of the one step reaction to get betrixaban.

As can be seen from the comparison of the table above, the reaction yields of betrixaban obtained in CN101595092B and CN102762538B are both significantly lower than that of the present invention; wherein, the betrixaban obtained by the method of CN101595092B has low purity and high contents of dechlorination impurities and monomethylamine impurities. CN102762538B also uses a large amount of water to wash the condensing agent in this step, and correspondingly generates a large amount of waste water; although the obtained product has good quality, the serious defect of low yield cannot be compensated.

The preparation method of the invention does not use the aprotic solvent in CN101595092B, only uses the protic solvent-liquefied dimethylamine, has single solvent, avoids the use of mixed solvent, is convenient for later recovery and reuse, and can reduce the amount of three wastes. In addition, the preparation method has the most obvious advantages that the generation of the monoammonium impurity and the dechlorination impurity can be basically avoided, the subsequent refining process is greatly simplified, and the production cost can be greatly reduced.

By "substantially" is meant that the content of monomethylamine impurities or dechlorinated impurities in betrixaban is below o.15%, preferably below 0.1%.

Therefore, the invention provides a simple and efficient preparation method of betrixaban, which is very suitable for industrial production.

Drawings

The invention will be further explained with reference to the drawings.

Fig. 1 is an HPLC profile of betrixaban prepared in example 7, in which peak No. 1 is a peak of betrixaban and peak No. 2 is a monomethylamine impurity peak.

Figure 2 is a nmr hydrogen spectrum of betrixaban prepared in example 7.

Fig. 3 is an HPLC profile of betrixaban prepared in comparative example 1, in which peak No. 1 is a peak of betrixaban, peak No. 2 is a monomethylamine impurity peak, and peak No. 3 is a dechlorinated impurity peak.

Fig. 4 is an HPLC profile of betrixaban prepared in comparative example 2, in which peak No. 1 is a peak of betrixaban, peak No. 2 is a monomethylamine impurity peak, and peak No. 3 is a dechlorinated impurity peak.

Detailed Description

The invention is illustrated below with reference to specific examples. It will be understood by those skilled in the art that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

The experimental procedures in the following examples are all conventional ones unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.

The purity of the betrixaban prepared in each of the following examples was determined by high performance liquid chromatography. The HPLC and chromatographic conditions were as follows:

a high performance liquid chromatograph:

a chromatographic column: c18, 4.6X 250mm

Mobile phase:

mobile phase A:1g ammonium acetate was dissolved in 1000ml water and adjusted to pH 3.0 with acetic acid

And (3) mobile phase B: acetonitrile

Gradiometer:

time (min)	Mobile phase A	Mobile phase B
			0	70	30
60	10	90

Detection wavelength: 240nm

Example 1Dimethylaminolithium (LiN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to-15 to-10 ℃, 256ml of butyl lithium solution (2.5 mol/L,0.64 mol) is dripped, and the dimethyl lithium solution is obtained for standby after heat preservation and stirring for 30min after dripping.

Example 2Dimethylaminolithium (LiN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to minus 10 ℃ to minus 5 ℃, 268ml of hexyl lithium solution (2.5 mol/L,0.67 mol) is dripped, and the dimethyl amino lithium solution is obtained for standby after heat preservation and stirring for 30min after dripping.

Example 3Dimethylamino magnesium chloride (MgClN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to minus 5 ℃ to 0 ℃, 335ml of n-propyl magnesium chloride solution (2.0 mol/L,0.67 mol) is dripped, and the dimethylamino magnesium chloride solution is obtained for standby after the dripping is finished and the heat preservation and the stirring are carried out for 1 h.

Example 4Dimethylamino magnesium chloride (MgClN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to minus 5-0 ℃, 325ml of phenylmagnesium chloride solution (2.0 mol/L,0.65 mol) is dripped, and the temperature is kept and the mixture is stirred for 3 hours after dripping to obtain the dimethylamino magnesium chloride solution for later use.

Example 5dimethylamino-Aumamizia (MgBrN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to minus 5 ℃ to 0 ℃, 670ml of isopropyl magnesium australia solution (1.0 mol/L,0.67 mol) is added dropwise, and the temperature is kept and the mixture is stirred for 1h after the dropwise addition to obtain dimethylamino magnesium australia solution for standby.

Example 6dimethylamino-Aumamizia (MgBrN (CH) ₃ ) ₂ ) Preparation of

Under the protection of nitrogen, 30g of liquefied dimethylamine (0.67 mol) is put into a reaction bottle, cooled to minus 5 ℃ to 0 ℃, 600ml of n-amyl magnesium australia solution (1.0 mol/L,0.6 mol) is added dropwise, and the mixture is stirred for 1.5 hours after heat preservation to obtain the dimethylamino magnesium australia solution for standby.

Example 7Preparation of betrixaban

450ml of liquefied dimethylamine and 30g of a compound (0.074 mol) with a structural formula II are put into a reaction bottle, cooled to-10 to-5 ℃, stirred, dropwise added with 0.36mol of the dimethylamino lithium solution prepared in the example 1, kept warm for 30min after dropwise addition, heated to 10-15 ℃, recovered dimethylamine, added with 300ml of aqueous solution containing 30g of sodium carbonate and 30g of sodium bicarbonate after recovery, stirred for 1h and filtered. The solid was slurried twice with methanol and dried to give betrixaban (31.9 g, 95.74% yield, 99.9% purity).

The HPLC profile and nmr hydrogen profile of betrixaban are shown in fig. 1 and fig. 2, respectively.

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.31-8.22(m，2H)，8.20-8.10(m，3H)，7.80(dd，1H)，7.77-7.70(m，2H)，7.42(d，1H)，7.17(dd，1H)，3.87(s，3H)，3.33(s，3H)，3.10(s，3H).

Example 8Preparation of betrixaban

300ml of liquefied dimethylamine and 30g of the compound (0.074 mol) of the structural formula II are put into a reaction bottle, cooled to-15 to-10 ℃, stirred, dropwise added with the dimethyl amino lithium solution (0.22 mol) prepared in the example 2, kept warm for 30min after dropwise addition, heated to 10-15 ℃, recovered dimethylamine, added with 300ml of sodium carbonate (30 g) and sodium bicarbonate (30 g) aqueous solution after recovery, stirred for 1h and filtered. The solid was slurried twice with methanol and dried to give betrixaban (31.3 g, 93.94% yield, 99.9% purity).

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.35-8.27(m，2H)，8.22-8.14(m，3H)，7.87(dd，2.6Hz，1H)，7.81-7.73(m，2H)，7.42(d，1H)，7.22(dd，1H)，3.92(s，3H)，3.39(s，3H)，3.15(s，3H).

The HPLC profile and nmr hydrogen profile of betrixaban prepared in this example are very similar to those of example 7 (profile omitted).

Example 9Preparation of betrixaban

350ml of liquefied dimethylamine and 30g of the compound (0.074 mol) of the structural formula II are put into a reaction bottle, cooled to minus 5-0 ℃, stirred, dropwise added with the dimethylamino magnesium chloride solution (0.5 mol) prepared in the example 3, kept warm for 30min after dropwise addition, heated to 10-15 ℃ to recover the dimethylamine, added with 300ml of sodium carbonate (30 g) and sodium bicarbonate (30 g) aqueous solution after recovery, stirred for 1h and filtered. The solid was slurried twice with methanol and dried to give betrixaban (30.2 g, yield 90.64%, purity 99.6%).

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.29-8.20(m，2H)，8.19-8.10(m，3H)，7.77(dd，1H)，7.73-7.69(m，2H)，7.39(d，1H)，7.18(dd，1H)，3.89(s，3H)，3.31(s，3H)，3.09(s，3H).

Example 10Preparation of betrixaban

350ml of liquefied dimethylamine and 30g of structural formula II (0.074 mol) are put into a reaction bottle, cooled to minus 5-0 ℃, stirred, dropwise added with the dimethylamino magnesium bromide solution (0.44 mol) prepared in example 5, kept warm for 30min after dropwise addition, heated to 10-15 ℃, recovered dimethylamine, added with 300ml of sodium carbonate (30 g) and sodium bicarbonate (30 g) aqueous solution after recovery, stirred for 1h and filtered. The solid was slurried twice with methanol and dried to give betrixaban (30.6 g, 91.84% yield, 99.7% purity).

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.30-8.23(m，2H)，8.19-8.08(m，3H)，7.79(dd，1H)，7.75-7.68(m，2H)，7.40(d，1H)，7.13(dd，1H)，3.82(s，3H)，3.29(s，3H)，3.08(s，3H).

Comparative example 1Betriciban is prepared according to patent CN101595092B example 2

The preparation process of the dimethyl amino lithium comprises the following steps: 24ml of a 2.3N hexyllithium hexane solution (0.56 mol) was added to 280ml of a 2N dimethylamine tetrahydrofuran solution (0.56 mol) and cooled to < 10 ℃.

500g of tetrahydrofuran and 45g of the compound of formula II (0.11 mol) are introduced into a reaction flask and cooled to < 10 ℃. The dimethyl amino lithium solution is dropped into the solution with the structural formula II, and the internal temperature is controlled to be less than 10 ℃. The HPLC detection reaction is complete (structural formula II is less than or equal to 1.0%). The reaction solution is added into sodium bicarbonate and sodium carbonate aqueous solution, the internal temperature is controlled to be less than or equal to 5 ℃, the stirring is carried out for 12 hours, and the temperature is slowly increased to 20 ℃. Filtration, water washing, ethanol rinsing, and drying yielded betrixaban (35.9 g, yield 71.8%, purity 98.5%).

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.30-8.21(m，2H)，8.20-8.11(m，3H)，7.72(dd，1H)，7.69-7.62(m，2H)，7.31(d，1H)，7.10(dd，1H)，3.81(s，3H)，3.28(s，3H)，3.09(s，3H)

The HPLC profile of betrixaban prepared in this comparative example is shown in fig. 3, in which peak No. 1 is the peak of betrixaban, peak No. 2 is the monomethylamine impurity peak, and peak No. 3 is the dechlorinated impurity peak.

Comparative example 2Betriciban prepared according to patents CN102762538B, example 5 and example 6

Step 1: preparation of amidine:

24ml of a 2.3N hexyllithium hexane solution (0.56 mol) was added dropwise to 280ml of a 2N dimethylamine-tetrahydrofuran solution (0.56 mol) at an internal temperature of-8 to-12 ℃. The above solution was dropped into 19.3g of a tetrahydrofuran solution of the structural formula H-1 (0.11 mol) in 200 ml. HPLC detects the reaction completely, and the temperature is increased to-8-3 ℃. The reaction mixture was slowly added to an aqueous sodium bicarbonate solution and extracted with ethyl acetate, which was evaporated under reduced pressure to give ethyl 4- (N, N-dimethylcarbamimidoyl) benzoate (19.5 g, yield 80.3%, purity 99.1%).

And 2, step: ester hydrolysis

Into a reaction flask, 150ml of tetrahydrofuran, 15G of an aqueous solution of the structural formula G-1 (0.07 mol), 12.3G of KOH (0.22 mol) were charged and reacted for 6 hours with stirring. The reaction was complete by HPLC, water was added, extracted with ethyl acetate, adjusted pH =3-4 with 6N HCl, filtered, and washed with N-hexane to give 4- (N, N-dimethylcarbamimidoyl) benzoate (formula a) (5.2 g, 39.7% yield, 99.3% purity).

And 3, step 3: synthesis of betrixaban

4g of formula IV (0.01 mol), 3.96g of formula A (0.02 mol) and 40ml of N, N-dimethylacetamide are placed in a reaction flask. After stirring, 72ml of concentrated hydrochloric acid was added. EDC.HCl (3.6 g) was added in three portions, 1.2g each, at 20 minute intervals. The reaction was stirred for 1.5 hours to completion.

The internal temperature was controlled at 22-30 ℃ and 4.6g of sodium carbonate/20 ml of water was added to the reaction solution, followed by vigorous stirring, 20ml of water was added, and stirring was carried out at 22-25 ℃ for 30 minutes. 40ml of water was added thereto, and the mixture was stirred for 1 hour. Filtering, washing filter cake with water and acetone, drying to obtain crude betrixaban (5.79 g, 89.1% yield and 97.6% purity).

5g of crude betrixaban, 20mlN and N-dimethylacetamide are put into a reaction bottle, and the temperature is increased to 70 ℃ and the mixture is stirred for 30 minutes. 40ml of toluene was added thereto, and the mixture was stirred for 30 minutes. Cooled to 22 ℃ and then cooled to 0 ℃ and stirred for 2 hours. Filtration, washing of the filter cake with toluene and drying yielded betrixaban (4.5 g, yield 90%, purity 99.3%).

MS：451.8[M+H] ⁺

¹ H NMR(400MHz，Methanol-d ₄ )δ8.35-8.26(m，2H)，8.20-8.13(m，3H)，7.74(dd，1H)，7.69-7.63(m，2H)，7.34(d，1H)，7.17(dd，1H)，3.84(s，3H)，3.32(s，3H)，3.12(s，3H)

The HPLC profile of betrixaban prepared in this comparative example is shown in fig. 4, in which peak No. 1 is the peak of betrixaban, peak No. 2 is the monomethylamine impurity peak, and peak No. 3 is the dechlorinated impurity peak.

Table 2 shows a comparison of example 7, comparative example 1 and comparative example 2 of the present invention in terms of betrixaban yield, HPLC purity, related impurity content, etc.

Table 2 comparison of product data relating to example 7 and comparative examples 1 and 2

	Comparative example 1	Comparative example 2	Method of example 7
				Yield of betrixaban	71.8％	80.2％ ^a	95.74％
HPLC purity	98.5％	99.3％	99.9％
				Dechlorinated impurities	0.95％	0.02％	Undetected
Monomethylamine impurity	0.43％	0.26％	0.06％

^a : comparative example 2 total yield of step 3.

The data in table 2 show that the preparation method of betrixaban provided by the invention has high yield and highest product purity, and the contents of dechlorinated impurities and monomethylamine impurities are obviously lower than those of the products prepared by the prior art.

Claims

1. A preparation method of betrixaban comprises the following steps:

I. under the protection of nitrogen, liquid dimethylamine reacts with one of n-butyl lithium, tert-butyl lithium, hexyl lithium, n-propyl magnesium chloride, isopropyl magnesium chloride, cyclohexyl magnesium chloride, phenyl magnesium chloride, benzyl magnesium chloride, methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide, isobutyl magnesium bromide, n-pentyl magnesium bromide, cyclopentyl magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl magnesium bromide, 4-diphenyl magnesium bromide, 4-phenoxyphenyl magnesium bromide, 4-fluorophenyl magnesium bromide, 4-chlorophenyl magnesium bromide and methyl magnesium iodide at the temperature of below 0 ℃ to prepare MN (CH) ₃ ) ₂ A dimethylamine solution of (a);

contacting a compound of formula II or a salt thereof with MN (CH) prepared in step I in the presence of a protic solvent only liquid dimethylamine ₃ ) ₂ Reacting the dimethylamine solution to obtain the betrixaban with a structural formula I; the molar ratio of the compound of formula II or a salt thereof to MN (CH 3) 2 is 1; the reaction temperature is less than or equal to 5 ℃;

wherein M = Li or MgX; wherein, X is selected from one of Cl, br and I.

2. Preparation method according to claim 1, characterized in that said MN (CH) ₃ ) ₂ The dimethylamine solution of (a) was prepared by the following method:

under the protection of nitrogen, liquid dimethylamine reacts with one of n-butyl lithium, tert-butyl lithium, hexyl lithium, isopropyl magnesium chloride, isopropyl magnesium bromide and n-pentyl magnesium bromide at the temperature of below 0 ℃.

3. The method of claim 1, wherein the reaction temperature is 0 ℃ or less.