CN104086527B

CN104086527B - A kind of synthetic method of SYR-322

Info

Publication number: CN104086527B
Application number: CN201410312805.XA
Authority: CN
Inventors: 莫国宁
Original assignee: HUNAN OUYA BIOLOGICAL CO Ltd
Current assignee: Hunan Eurasia Pharmaceutical Co., Ltd.
Priority date: 2014-07-03
Filing date: 2014-07-03
Publication date: 2016-09-21
Anticipated expiration: 2034-07-03
Also published as: CN104086527A

Abstract

The invention discloses the synthetic method of a kind of SYR-322; with (R) 3 Boc amino piperidine and monoethyl malonate as raw material; carry out amidation process; synthesis obtains (R) 3 (3 Boc amino piperidine 1 base) 3 oxopropanoate; carry out ring closure reaction with 1 (2 cyanobenzyls) 3 MUs again, then pass through acid condition deprotection, obtain Egelieting; finally become salt with benzoic acid, prepare SYR-322.The present invention simplifies and optimizes synthetic route and technique, and reagent is easy to get, and reduces cost, and total recovery is higher, can produce in a large number and meet use demand, is a kind of high effective green environmentally friendly process, it is adaptable to industrialized production.

Description

A kind of synthetic method of SYR-322

Technical field

The present invention relates to pharmaceutical chemistry synthesis field, the synthetic method of a kind of SYR-322.

Background technology

The entitled 2-of chemistry [6-(3 (R)-amino piperidine-1-of SYR-322 (Alogliptin benzoate, I) Base)-3-methyl-2,4-dioxygen generation-1,2,3,4-tetrahydropyrimidine-1-ylmethyls] benzonitrile benzoic acid salt, its chemical structural formula For:

It is that a kind of high selective serine protease DPP IV (DPP-IV) that Wu Tian company of Japan researches and develops presses down Preparation, can maintain internal incretin sample peptide GLP-1-1(glucagon-like peptide-1) and glucose dependency rush pancreas Island element polypeptide GIP(glucose-dependent insulinotropic peptide) level, promote insulin secretion, Play blood sugar lowering curative effect, for the glycemic control of type 2 diabetes mellitus patient, for oral medication type 2 diabetes mellitus medicine.

Patent WO2007035629 and CN101360723 disclose a kind of preparation method of SYR-322: with 6- Chloro-3-methyluracil and 2-bromomethyl benzonitrile are initiation material, by condensation, then contract with (R)-3-amino piperidine dihydrochloride Closing, become salt, prepare SYR-322 (I), process route is as follows:

In the disclosed Egelieting preparation method such as patent WO2005095381, EP1586571 and CN102134231, change It is initiation material with 6-chlorouracil, after condensation reaction, then methylates on NH position, then with (R)-3-amino piperidine Dihydrochloride condensation reaction, prepares Egelieting (IV), and synthetic route is as follows:

And patent CN103664801 uses and realizes methylation process by Mitsunobu reaction.In above-mentioned technique, need big Amount uses sodium hydride and lithium bromide, react higher to the requirement of anhydrous and oxygen-free, and iodomethane toxicity is relatively big, be unfavorable for environmental conservation with Amplification quantity produces, and on the other hand, owing to (R)-3-amino piperidine dihydrochloride has two amino, all can directly participate in condensation, with And the unstability at condensation reaction, cause being inevitably generated side reaction, affect product quality, need to pass through post Chromatography separates and purification, complex operation, is unfavorable for that amplification quantity produces and industrial operation.

Preparing in SYR-322 process route of patent CN102942556, use (R)-3-amino of Boc protection instead Piperidines:

Dock second time condensation reaction.

In SYR-322 preparation method disclosed in patent WO2010109468 and CN102361557, the first work Skill is first to prepare urea derivative with 2-(aminomethyl) cyanophenyl, and malonic acid (or its diethylester) carries out ring closure reaction, then chlorine The reaction such as generation, condensation prepares SYR-322 (I), and synthetic route is as follows:

Owing to chlorination employs highly toxic phosphorus oxychloride, have greater environmental impacts；The second technique uses cyano group instead Acetic acid, docks condensation with urea derivative, then carries out ring closure reaction:

Although Avoid phosphorus oxychloride, but the cyanoacetic acid used also has very high toxicity, simultaneously because whole synthetic route step is longer, Relatively costly, it is unfavorable for that industrialization produces and promotes.Be necessary for this to develop a kind of new operation simplify, with low cost, applicable The SYR-322 synthetic method of industrialized production.

Summary of the invention

For the deficiencies in the prior art and defect, it is an object of the invention to provide a kind of SYR-322 Synthetic method.

For achieving the above object, the present invention provides following technical scheme:

The synthetic method of a kind of SYR-322, is former with (R)-3-Boc-amino piperidine and monoethyl malonate Material, carries out amidation process, and synthesis obtains (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate, then with 1- (2-cyanobenzyls)-3-MU carries out ring closure reaction, then passes through acid condition deprotection, obtains Egelieting, last with Benzoic acid becomes salt, prepares SYR-322 (I), including following synthesis step:

(1) it is that raw material carries out amidation process with (R)-3-Boc-amino piperidine and monoethyl malonate, wherein the third two Acid mono ethyl ester is 1.0 ~ 1.5:1 with the inventory mol ratio of (R)-3-Boc-amino piperidine, alkali and (R)-3-Boc-amino piperidine Inventory mol ratio be 1.0 ~ 1.8:1, reaction temperature is-10 ~ 10 DEG C, and the response time is 1 ~ 6 hour, synthesis obtain (R)-3- (3-Boc-amino piperidine-1-base)-3-oxopropanoate (II), reaction equation is:

Wherein, solvent is oxolane, methyl tertiary butyl ether(MTBE), DMF i.e. DMF, N, N-diethyl formyl Amine i.e. DMA, 1,4-dioxane or acetonitrile；Alkali is organic amine alkali such as triethylamine, diethylamine, N, N-diisopropylethylamine, pyrrole Pyridine, piperidines, tri-n-butylamine, trimethylamine, Tris(isopropylamine)., aniline, N, N-dimethylaniline, N, N-diethylaniline, 2,6-dimethyl Pyridine, DMAP, tetramethyl guanidine, N-methylmorpholine, two cyclohexyl amines；

(2) (R)-3-(3-Boc-amino piperidine-1-the base)-3-oxopropanoate (II) obtained by step (1), with 1-(2-cyanobenzyls)-3-MU carries out ring closure reaction, wherein base reagent and (R)-3-(3-Boc-under the catalysis of base reagent Amino piperidine-1-base) the inventory mol ratio of-3-oxopropanoate (II) is 1.0 ~ 1.6:1, reaction temperature is 50 ~ 100 DEG C, the response time is 4 ~ 12 hours；Obtaining the precursor (III) of Egelieting, reaction equation is:

Wherein, base reagent is metallic sodium, sodium hydride, hydrofining, Feldalat NM, Sodium ethylate or sodium tert-butoxide；Solvent is methanol, second Alcohol, isopropanol, normal propyl alcohol or the tert-butyl alcohol；

(3) product (III) obtained by step (2) is deprotected by acid condition, wherein acid and the precursor of Egelieting (III) inventory mol ratio is 1.0 ~ 1.5:1, and reaction temperature is 50 ~ 80 DEG C, and the response time is 4 ~ 10 hours, obtains A Ge Row spit of fland (IV), reaction equation is:

Wherein, solvent is methanol, ethanol, dichloromethane, ethyl acetate, oxolane or dioxane；Acid is trifluoro second Acid, trifluoacetic anhydride, hydrochloric acid, p-methyl benzenesulfonic acid or methanesulfonic acid；

(4) Egelieting (IV) obtained by step (3) becomes salt with benzoic acid, prepares SYR-322 (I), wherein reaction temperature is 50 ~ 100 DEG C, and the response time is 4 ~ 12 hours, and reaction equation is:

Wherein, organic solvent is ethers, alcohols, amide-type, sulfone kind solvent or their mixture.

As the further scheme of the present invention: monoethyl malonate and the throwing of (R)-3-Boc-amino piperidine in step (1) Doses mol ratio is 1.1 ~ 1.2:1, and described alkali is 1.1 ~ 1.5:1 with the inventory mol ratio of (R)-3-Boc-amino piperidine.

As the further scheme of the present invention: described in step (1), the reaction temperature of amidation process is-5 ~ 5 DEG C, reaction Time is 2 ~ 4 hours.

As the further scheme of the present invention: base reagent and (R)-3-(3-Boc-amino piperidine-1-base) in step (2)- The inventory mol ratio of 3-oxopropanoate (II) is 1.1 ~ 1.3:1.

As the further scheme of the present invention: described in step (2), the reaction temperature of ring closure reaction is 60 ~ 80 DEG C, reaction Time is 6 ~ 9 hours.

As the further scheme of the present invention: the inventory mol ratio of the precursor (III) of acid and Egelieting in step (3) It is 1.1 ~ 1.3:1.

As the further scheme of the present invention: in step (3), reaction temperature is 60 ~ 70 DEG C, the response time is 6 ~ 8 hours.

As the further scheme of the present invention: in step (4), reaction temperature is 60 ~ 80 DEG C, the response time is 6 ~ 9 hours.

Compared with prior art, the invention has the beneficial effects as follows: the synthetic method of the SYR-322 of the present invention, letter Changing and optimize synthetic route and technique, reagent is easy to get, and reduces cost, and total recovery is higher, can produce in a large number and meet use Demand, is a kind of high effective green environmentally friendly process, it is adaptable to industrialized production.

Detailed description of the invention

Below in conjunction with the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described, Obviously, described embodiment is only a part of embodiment of the present invention rather than whole embodiments.Based in the present invention Embodiment, the every other embodiment that those of ordinary skill in the art are obtained under not making creative work premise, all Belong to the scope of protection of the invention.

In the embodiment of the present invention, the synthetic method of a kind of SYR-322, with (R)-3-Boc-amino piperidine and third Diacid mono ethyl ester is raw material, carries out amidation process, and synthesis obtains (R)-3-(3-Boc-amino piperidine-1-base)-3-oxo third Acetoacetic ester, then carry out ring closure reaction with 1-(2-cyanobenzyls)-3-MU, then pass through acid condition deprotection, obtain Ah Ge Lieting, finally becomes salt with benzoic acid, prepares SYR-322 (I), including following synthesis step:

(1) it is that raw material carries out amidation process with (R)-3-Boc-amino piperidine and monoethyl malonate, wherein the third two The inventory mol ratio of acid mono ethyl ester and (R)-3-Boc-amino piperidine is 1.0 ~ 1.5:1, preferably: 1.1 ~ 1.2:1, and alkali and (R)- The inventory mol ratio of 3-Boc-amino piperidine is 1.0 ~ 1.8:1, and preferably: 1.1 ~ 1.5:1, reaction temperature is-10 ~ 10 DEG C, excellent Choosing :-5 ~ 5 DEG C, the response time is 1 ~ 6 hour, preferably: 2 ~ 4 hours, synthesis obtain (R)-3-(3-Boc-amino piperidine-1-base)- 3-oxopropanoate (II), reaction equation is:

(2) (R)-3-(3-Boc-amino piperidine-1-the base)-3-oxopropanoate (II) obtained by step (1), with 1-(2-cyanobenzyls)-3-MU carries out ring closure reaction, wherein base reagent and (R)-3-(3-Boc-under the catalysis of base reagent Amino piperidine-1-base) the inventory mol ratio of-3-oxopropanoate (II) is 1.0 ~ 1.6:1, preferably: 1.1 ~ 1.3:1, instead Answering temperature is 50 ~ 100 DEG C, and preferably: 60 ~ 80 DEG C, the response time is 4 ~ 12 hours, preferably: 6 ~ 9 hours, obtain Egelieting Precursor (III), reaction equation is:

Wherein, base reagent is metallic sodium, sodium hydride, hydrofining, Feldalat NM, Sodium ethylate or sodium tert-butoxide；Solvent is methanol, ethanol, different Propanol, normal propyl alcohol or the tert-butyl alcohol；

(3) product (III) obtained by step (2) is deprotected by acid condition, wherein acid and the precursor of Egelieting (III) inventory mol ratio is 1.0 ~ 1.5:1, and preferably: 1.1 ~ 1.3:1, reaction temperature is 50 ~ 80 DEG C, preferably: 60 ~ 70 DEG C, Response time is 4 ~ 10 hours, preferably: 6 ~ 8 hours, obtains Egelieting (IV), and reaction equation is:

(4) Egelieting (IV) obtained by step (3) becomes salt with benzoic acid, prepares SYR-322 (I), wherein reaction temperature is 50 ~ 100 DEG C, preferably: 60 ~ 80 DEG C, and the response time is 4 ~ 12 hours, preferably: 6 ~ 9 hours, reaction Formula is:

Embodiment 1

The synthetic method of a kind of SYR-322, comprises the following steps:

(1) synthesis of (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate (II)

Adding the monoethyl malonate of 89.0g in reaction bulb, add the thionyl chloride of 200mL, stirring and dissolving, nitrogen is protected Protecting, stir 2 hours at 25 DEG C, rotation is steamed and is removed remaining thionyl chloride to dry, obtains the monoethyl malonate of pale yellow oil Acyl chlorides, (R)-3-Boc-amino piperidine of 122.5g is dissolved in the oxolane of 1.8L, adds the triethylamine of 107mL, and ice bath cools down To 0 DEG C, dripping monoethyl malonate acyl chlorides, it is complete that equality of temperature reacts extremely reaction in 3 hours, and vacuum rotary steam is concentrated to dryness, and adds 1L's The water extraction of ethyl acetate and 1L, is layered organic facies, and successively with saturated sodium bicarbonate solution and salt washing, anhydrous sodium sulfate is done Dry, vacuum rotary steam is concentrated to dryness, crude oil ethyl alcohol recrystallization, and 60 DEG C are vacuum dried 12 hours, obtains off-white color to yellowish Color pulverulent solids 167.0g, yield 87%, purity 98.5%.

(2) synthesis of the precursor (III) of Egelieting

1-(2-cyanobenzyls)-3-MU is prepared according to the method for patent WO2010109468 and CN102361557.

The Sodium ethylate of 36.0g is dissolved in the dehydrated alcohol of 600mL, and nitrogen is protected, and stirs, and (R) of addition 150.0g- 3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate (II) and 1-(2-the cyanobenzyls)-3-MU of 90.3g, rise Temperature backflow is down to room temperature in 6 hours to reaction completely, and dropping dilute hydrochloric acid adjusts pH=7, and vacuum rotary steam is concentrated to dryness, and adds 800mL's The water extraction of ethyl acetate and 800mL, is layered organic facies, and anhydrous sodium sulfate is dried, and vacuum rotary steam is concentrated to dryness, isopropanol-second Alcohol mixed solvent recrystallization, 60 DEG C are vacuum dried 12 hours, obtain off-white color to pale yellow powder shape solid 164.8g, yield 79%, Purity 99.3%.

(3) synthesis of Egelieting (IV)

The precursor (III) of Egelieting and the methanol of 2L of 160.0g, 0.36mol is added in reaction bulb, stirring and dissolving, Adding the trifluoroacetic acid of 46.0g, 65 DEG C of stirring reactions are extremely reacted completely for 7 hours, and reactant liquor is added drop-wise in the 2L water of stirring, stirring After 30 minutes, filter, filter cake and saturated sodium bicarbonate solution mix and blend 30 minutes, filter, wash filter cake, isopropanol-ethanol Mixed solvent recrystallization, 60 DEG C are vacuum dried 12 hours, obtain off-white color solid 102.5g, yield 83%, purity 98.9%, fusing point 126~128℃。

(4) synthesis of SYR-322 (I)

In reaction bulb, add Egelieting (IV) and the dehydrated alcohol of 2.5L of 100.0g, stirring and dissolving, add 54.0g Benzoic acid, system reactant liquor rise to return stirring react 6 hours to reaction completely, be cooled to room temperature, solid separates out, and is cooled to 5 ~ 10 DEG C, crystallize 2 hours, filter, filter cake isopropanol-ethyl alcohol recrystallization, 60 DEG C are vacuum dried 12 hours, obtain white solid SYR-322 (I) 121.7g, yield 90%, purity 99.5%, fusing point 178 ~ 180 DEG C.

Embodiment 2

The synthetic method of a kind of SYR-322, comprises the following steps:

(1) synthesis of (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate (II)

Adding the monoethyl malonate of 158.0g and the thionyl chloride of 377mL, stirring and dissolving in reaction bulb, nitrogen is protected Protecting, stir 2 hours at 25 DEG C, rotation is steamed and is removed remaining thionyl chloride to dry, obtains the monoethyl malonate of pale yellow oil Acyl chlorides, (R)-3-Boc-amino piperidine of 200.0g is dissolved in the methyl tertiary butyl ether(MTBE) of 2.5L, and the N, N-bis-adding 230mL is different Propylethylamine, ice bath is cooled to 5 DEG C, drips monoethyl malonate acyl chlorides, and it is complete that equality of temperature reacts extremely reaction in 4 hours, vacuum rotary steam Be concentrated to dryness, add the water extraction of the ethyl acetate of 1.2L and 1.2L, be layered organic facies, successively with saturated sodium bicarbonate solution and Salt is washed, and anhydrous sodium sulfate is dried, and vacuum rotary steam is concentrated to dryness, crude oil ethyl alcohol recrystallization, 60 DEG C of vacuum drying 12 Hour, obtain off-white color to pale yellow powder shape solid 282.5g, yield 90%, purity 98.4%.

(2) synthesis of the precursor (III) of Egelieting

The metallic sodium of 22.0g is dissolved in the methanol of 1.2L, and nitrogen is protected, and under room temperature, stirring makes the reaction of sodium sheet completely, ice bath It is cooled to 15 DEG C, adds (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate (II) and the 150.0g of 250.0g 1-(2-cyanobenzyls)-3-MU, temperature rising reflux 7 hours to reaction completely, is down to room temperature, dropping dilute hydrochloric acid adjust pH=6 ~ 7, vacuum rotary steam is concentrated to dryness, and adds the ethyl acetate of 1L and the water extraction of 1L, is layered organic facies, and anhydrous sodium sulfate is dried, and subtracts Pressure concentrated by rotary evaporation is to dry, and isopropanol-alcohol mixed solvent recrystallization, 60 DEG C are vacuum dried 12 hours, obtain off-white color to faint yellow Pulverulent solids 286.0g, yield 82%, purity 99.5%.

(3) synthesis of Egelieting (IV)

In reaction bulb, add precursor (III) and the ethyl acetate of 3L of the Egelieting of 250.0g, stirring and dissolving, add The p-methyl benzenesulfonic acid of 127.0g, it is complete that temperature rising reflux reacts extremely reaction in 8 hours, and reactant liquor is added drop-wise in the 2L water of stirring, stirring After 30 minutes, filter, filter cake and saturated sodium bicarbonate solution mix and blend 20 minutes, filter, wash filter cake, isopropanol-ethanol Mixed solvent recrystallization, 60 DEG C are vacuum dried 12 hours, obtain off-white color solid 154.0g, yield 80%, purity 99.1%, fusing point 127~128℃。

(4) synthesis of SYR-322 (I)

In reaction bulb, add Egelieting (IV) and the oxolane of 3L of 150.0g, stirring and dissolving, add 75.0g's Benzoic acid, rises to return stirring reaction extremely reaction in 8 hours and completely, is cooled to room temperature, and solid separates out, and is cooled to 5 ~ 10 DEG C, crystallize 3 Hour, filter, filter cake isopropanol-ethyl alcohol recrystallization, 60 DEG C are vacuum dried 12 hours, obtain the benzoic acid A Gelie of white solid Spit of fland (I) 177.8g, yield 87%, purity 99.6%, fusing point 179 ~ 180 DEG C.

It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie In the case of the spirit or essential attributes of the present invention, it is possible to realize the present invention in other specific forms.Therefore, no matter From the point of view of which point, all should regard embodiment as exemplary, and be nonrestrictive, the scope of the present invention is by appended power Profit requires rather than described above limits, it is intended that all by fall in the implication of equivalency and scope of claim Change is included in the present invention.

Although moreover, it will be appreciated that this specification is been described by according to embodiment, but the most each embodiment only wraps Containing an independent technical scheme, this narrating mode of description is only that for clarity sake those skilled in the art should Description can also be formed those skilled in the art through appropriately combined as an entirety, the technical scheme in each embodiment May be appreciated other embodiments.

Claims

1. the synthetic method of a SYR-322, it is characterised in that with (R)-3-Boc-amino piperidine and malonic acid list Ethyl ester is raw material, carries out amidation process, and synthesis obtains (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate, Carry out ring closure reaction with 1-(2-cyanobenzyls)-3-MU again, then pass through acid condition deprotection, obtain Egelieting, Finally become salt with benzoic acid, prepare SYR-322 (I), including following synthesis step:

(1) it is that raw material carries out amidation process, wherein malonic acid list second with (R)-3-Boc-amino piperidine and monoethyl malonate Ester is 1.0～1.5:1 with the inventory mol ratio of (R)-3-Boc-amino piperidine, and alkali feeds intake with (R)-3-Boc-amino piperidine Amount mol ratio is 1.0～1.8:1, and reaction temperature is-10～10 DEG C, and the response time is 1～6 hour, and synthesis obtains (R)-3-(3- Boc-amino piperidine-1-base)-3-oxopropanoate (II), reaction equation is:

Wherein, solvent be oxolane, methyl tertiary butyl ether(MTBE), DMF i.e. DMF, N,N-dimethylacetamide i.e. DMA, 1,4-dioxane or acetonitrile；Alkali is triethylamine, diethylamine, N, N-diisopropylethylamine, pyridine, piperidines, tri-n-butylamine, Trimethylamine, Tris(isopropylamine)., aniline, N, N-dimethylaniline, N, N-diethylaniline, 2,6-lutidines, 4-dimethylamino pyrrole Pyridine, tetramethyl guanidine, N-methylmorpholine；

(2) (R)-3-(3-Boc-amino piperidine-1-the base)-3-oxopropanoate (II) obtained by step (1), with 1-(2- Cyanobenzyls)-3-MU carries out ring closure reaction under the catalysis of base reagent, wherein base reagent and (R)-3-(3-Boc-amino Piperidin-1-yl) the inventory mol ratio of-3-oxopropanoate (II) is 1.0～1.6:1, reaction temperature is 50～100 DEG C, Response time is 4～12 hours；Obtaining the precursor (III) of Egelieting, reaction equation is:

(3) product (III) obtained by step (2) is deprotected by acid condition, wherein acid and the precursor (III) of Egelieting Inventory mol ratio be 1.0～1.5:1, reaction temperature is 50～80 DEG C, and the response time is 4～10 hours, obtains A Gelie Spit of fland (IV), reaction equation is:

Wherein, solvent is methanol, ethanol, dichloromethane, ethyl acetate, oxolane or dioxane；Acid be trifluoroacetic acid, three Fluorine acetic anhydride, hydrochloric acid, p-methyl benzenesulfonic acid or methanesulfonic acid；

(4) Egelieting (IV) obtained by step (3) becomes salt with benzoic acid, prepares SYR-322 (I), wherein Reaction temperature is 50～100 DEG C, and the response time is 4～12 hours, and reaction equation is:

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that malonic acid in step (1) Mono ethyl ester is 1.1～1.2:1 with the inventory mol ratio of (R)-3-Boc-amino piperidine, described alkali and (R)-3-Boc-amino piperazine The inventory mol ratio of pyridine is 1.1～1.5:1.

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that acyl described in step (1) The reaction temperature of aminating reaction is-5～5 DEG C, and the response time is 2～4 hours.

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that base reagent in step (2) It is 1.1～1.3:1 with the inventory mol ratio of (R)-3-(3-Boc-amino piperidine-1-base)-3-oxopropanoate (II).

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that close described in step (2) The reaction temperature of ring reaction is 60～80 DEG C, and the response time is 6～9 hours.

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that in step (3) acid and Ah The inventory mol ratio of the precursor (III) of Ge Lieting is 1.1～1.3:1.

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that reaction temperature in step (3) Degree is 60～70 DEG C, and the response time is 6～8 hours.

The synthetic method of SYR-322 the most according to claim 1, it is characterised in that reaction temperature in step (4) Degree is 60～80 DEG C, and the response time is 6～9 hours.