CN117567404A - 一种(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法 - Google Patents
一种(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法 Download PDFInfo
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- ZNQCEVIJOQZWLO-VURMDHGXSA-N (2z)-2-(furan-2-yl)-2-methoxyiminoacetic acid Chemical compound CO\N=C(/C(O)=O)C1=CC=CO1 ZNQCEVIJOQZWLO-VURMDHGXSA-N 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims abstract description 16
- LDPKPWSWBUFCLZ-ALCCZGGFSA-N O1C(=CC=C1)/C=N\OC Chemical compound O1C(=CC=C1)/C=N\OC LDPKPWSWBUFCLZ-ALCCZGGFSA-N 0.000 claims abstract description 13
- -1 2- (furan-2-yl) -2- (methoxyamino) acetonitrile Chemical compound 0.000 claims abstract description 12
- 239000002253 acid Substances 0.000 claims abstract description 8
- 239000011230 binding agent Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 claims abstract description 8
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 7
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000007333 cyanation reaction Methods 0.000 claims abstract description 4
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical group N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 abstract description 4
- 238000000746 purification Methods 0.000 abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
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- 229960001668 cefuroxime Drugs 0.000 description 6
- JFPVXVDWJQMJEE-IZRZKJBUSA-N cefuroxime Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 JFPVXVDWJQMJEE-IZRZKJBUSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 239000002994 raw material Substances 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
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- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- IXVPCJUAKDVYKX-UHFFFAOYSA-N 2-(furan-2-yl)-2-oxoacetic acid Chemical compound OC(=O)C(=O)C1=CC=CO1 IXVPCJUAKDVYKX-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- KEJCWVGMRLCZQQ-YJBYXUATSA-N Cefuroxime axetil Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OC(C)OC(C)=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 KEJCWVGMRLCZQQ-YJBYXUATSA-N 0.000 description 1
- URDOHUPGIOGTKV-JTBFTWTJSA-M Cefuroxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CC=CO1 URDOHUPGIOGTKV-JTBFTWTJSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
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- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960002620 cefuroxime axetil Drugs 0.000 description 1
- 229960000534 cefuroxime sodium Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明提供一种(Z)‑α‑(甲氧基亚氨基)呋喃‑2‑乙酸的制备方法,属于医药中间体领域。采用糠醛与甲氧胺盐酸盐在缚酸剂下缩合得到2‑呋喃甲醛O‑甲基肟,接着与氰基化试剂在DMSO中加成得到2‑(呋喃‑2‑基)‑2‑(甲氧基氨基)乙腈,随后用三氯化铁氧化得到(Z)‑N‑甲氧基呋喃‑2‑酰亚胺基氰化物,最后硫酸溶液水解得到(Z)‑α‑(甲氧基亚氨基)呋喃‑2‑乙酸。本发明制备方法具备步骤间操作连贯,收率高,纯度高达99%以上等优点;避免因构型造成的纯化困难、颜色等问题。
Description
技术领域
本发明涉及(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,属于医药中间体技术领域。
背景技术
(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸主要用于合成头孢菌素-头孢呋辛-头孢呋辛钠(供注射用)或头孢呋辛酯(供口服用)的重要中间体,即头孢呋辛的侧链。头孢呋辛属于头孢菌素类抗生素中第二代产品,主要应用于敏感的革兰阴性菌所致的下呼吸道、泌尿系、皮肤和软组织、骨和关节、女生殖器等部位的感染等。其特点是抗菌谱广、肾脏毒性较低、渗透性强、因在头孢菌素环上的7-位侧链链接有甲氧亚胺基,对β-内酰胺酶具有较高的稳定性和耐受性;
(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸与(Z)-2-甲氧基亚氨基-2-(呋喃-2-基)乙酸铵在头孢呋辛的生产过程中使用性质是一样的。(Z)-2-甲氧基亚氨基-2-(呋喃-2-基)乙酸铵是(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的铵盐,(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸也是头孢呋辛钠杂质I。
现有技术中,(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备主要通过α-氧代-2-呋喃乙酸与甲氧基胺肟化反应制得,反应方程式如下:
按照上述操作制备的(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸存在生产或储存及使用过程中容易吸潮结块,不容易纯化,颜色较深,往往需要与氨成盐制备(Z)-2-甲氧基亚氨基-2-(呋喃-2-基)乙酸铵,相比较而言(Z)-2-甲氧基亚氨基-2-(呋喃-2-基)乙酸铵晶型相比较更好,更容易储存,虽然解决了(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸顺反构型纯化问题。但增加了操作步骤,头孢呋辛缩合过程需要铵盐解离,造成人力物力的浪费。
为了弥补头孢呋辛的现有合成方法不足,有必要对(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法进行改进,开发出一种收率较高、成本较低、更适合工业化生产的合成路线。来避免异构体纯化和收率低的问题尤为重要,进而满足市场日益增长的需要。
发明内容
为了更好的解决上述问题,使(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸颜色、晶型及顺反异构问题得到解决,本发现提供一种(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,采用糠醛与甲氧胺盐酸盐在缚酸剂下缩合得到2-呋喃甲醛O-甲基肟,接着与氰基化试剂在DMSO中加成得到2-(呋喃-2-基)-2-(甲氧基氨基)乙腈,随后用三氯化铁氧化得到(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物,最后硫酸溶液水解得到(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸。本发明制备方法具备步骤间操作连贯,收率高,纯度高达99%以上等优点;避免因构型造成的纯化困难、颜色等问题。
为实现上述目的,化学制备(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的工艺,包括以下步骤:
步骤1):糠醛与甲氧胺盐酸盐混合在甲苯中,室温下缓慢加入缚酸剂,随后升温反应得到2-呋喃甲醛O-甲基肟;
步骤2):2-呋喃甲醛O-甲基肟与氰基化试剂在DMSO升温反应得到2-(呋喃-2-基)-2-(甲氧基氨基)乙腈;
步骤3):三氯化铁与甲醇混合,缓慢加入2-(呋喃-2-基)-2-(甲氧基氨基)乙腈与甲醇的混合溶液氧化得到(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物;
步骤4):(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物与硫酸混合,升温水解反应得到(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸。
反应方程式表示如下:
进一步地,步骤1)中所述缚酸剂选自吡啶或三乙胺。
进一步地,步骤1)中所述糠醛、甲氧胺盐酸盐和缚酸剂摩尔比例为1:1.15-1.20:1.20-1.22。
进一步地,步骤2)中所述氰基化试剂选自***、***或氰基三甲基硅烷。
进一步地,步骤2)中所述选自2-呋喃甲醛O-甲基肟与氰基化试剂摩尔比为1:1.4-1.8。
进一步地,步骤3)中所述2-(呋喃-2-基)-2-(甲氧基氨基)乙腈与三氯化铁摩尔比例为1:2.5-3.0。
进一步地,步骤4)中所述硫酸选自60-65%硫酸水溶液。
进一步地,步骤4)中所述(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物与硫酸摩尔比例为1:2.2-2.5。
发明有益效果
本发明提供的(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,解决了因构型造成的纯化困难,操作简单,最终高收率得到目标产物且纯度大于99.0%。
具体实施方式
为使本领域技术人员清楚明白本发明提供的头孢呋辛中间体(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,下面结合实施例进一步说明,但这些实施例不应被视作为对本发明保护范围的限制。
实施例1
向反应器中加入96.1g(1.0mol)糠醛、96.1g(1.15mol)甲氧胺盐酸盐和1000mL甲苯,温度控制在45-55℃,搅拌下缓慢滴加121.4g(1.20mol)三乙胺,然后60℃反应3小时,TLC原料无剩余,减压浓缩甲苯,加入600mL甲苯,过滤,甲苯洗涤滤饼,滤液用柠檬酸水溶液和饱和食盐水洗涤,无水硫酸镁干燥,过滤,甲苯洗涤滤饼,减压浓缩滤液至干得到2-呋喃甲醛O-甲基肟121.6g,收率97.2%,HPLC 97.7%。1H-NMR(400MHz,CDCl3):8.89(s,1H),7.84-7.80(m,1H),6.94-6.90(m,1H),6.64-6.60(m,1H),3.93(s,3H)。
实施例2
向反应器中加入96.1g(1.0mol)糠醛、96.1g(1.15mol)甲氧胺盐酸盐和1000mL甲苯,温度控制在45-55℃,搅拌下缓慢滴加96.5g(1.22mol)吡啶,然后60℃反应3小时,TLC原料无剩余,减压浓缩甲苯,加入600mL甲苯,过滤,甲苯洗涤滤饼,滤液用柠檬酸水溶液和饱和食盐水洗涤,无水硫酸镁干燥,过滤,甲苯洗涤滤饼,减压浓缩滤液至干得到2-呋喃甲醛O-甲基肟120g,收率95.9%,HPLC 98.3%。
实施例3
向连接尾气吸收的反应器中加入118.9g(0.95mol)2-呋喃甲醛O-甲基肟、83.3g(1.7mol)***、水68g和840mL DMSO,升温80-85℃反应3小时,TLC检测无原料剩余,搅拌下加入1000mL水淬灭和加入1100mL甲基叔丁基醚,反应液静置分层,分出有机相甲基叔丁基醚层用水洗涤(水相次氯酸钠溶液处理),饱和食盐水洗涤,减压浓缩甲基叔丁基醚,加入85%甲醇溶液重结晶,-10℃过滤,烘干得到2-(呋喃-2-基)-2-(甲氧基氨基)乙腈128.1g,收率88.6%,HPLC 98.7%。1H-NMR(400MHz,CDCl3):7.36-7.32(m,1H),6.29-6.12(m,2H),5.14(t,1H),3.57(s,3H),2.18(s,1H).
实施例4
向连接尾气吸收的反应器中加入118.9g(0.95mol)2-呋喃甲醛O-甲基肟、138.9g(1.4mol)氰基三甲基硅烷、0.5g氟化铯、水68g和840mL DMSO,升温80-85℃反应4小时,TLC检测无原料剩余,搅拌下加入1000mL水淬灭和加入1100mL甲基叔丁基醚,反应液静置分层,分出有机相甲基叔丁基醚层用水洗涤(水相用次氯酸钠溶液处理),饱和食盐水洗涤,减压浓缩甲基叔丁基醚,加入85%甲醇溶液重结晶,-10℃过滤,烘干得到2-(呋喃-2-基)-2-(甲氧基氨基)乙腈115.3g,收率79.8%,HPLC98.5%。
实施例5
向反应器中加入900mL甲醇,降温至-5℃,加入304.1g(1.875mol)三氯化铁,缓慢升温至10℃,缓慢滴加114.1g(0.75mol)2-(呋喃-2-基)-2-(甲氧基氨基)乙腈和200mL甲醇混合溶液,室温反应8小时,过滤,滤饼用甲醇淋洗,滤液减压浓缩甲醇,搅拌下加入700mL甲基叔丁基醚和800mL水,静置分层,有机相甲基叔丁基醚层用硫代硫酸钠水溶液和氯化钠水溶液洗涤,有机相无水硫酸镁干燥,过滤,滤液减压浓缩甲基叔丁基醚,加入庚烷析出晶体,过滤,烘干得到(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物102.1g,收率90.7%,HPLC 95.9%。1H-NMR(400MHz,CDCl3):7.84-7.80(m,1H),6.55-6.49(m,2H),3.95(s,3H).
实施例6
向反应器中加入165.8g(1.1mol)65%硫酸升温至55℃,分批加入75.1g(0.5mol)(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物,升温至85-90℃,搅拌反应6小时,HPLC检测原料剩余0.05%,加入300mL甲苯和350mL水,降温至50℃,加入20%氢氧化钠调节pH=12.5,该温度下静置分层,下层水相降温至0℃,缓慢滴加5%硫酸调节pH=2.0,加入200mL*3乙酸乙酯萃取水相,有机相减压浓缩乙酸乙酯,加入850mL甲苯浓缩替换一次,再加入850mL甲苯并升温至90-100℃,加入活性炭1.5g、100-200目硅胶8.5g,无水硫酸镁5g,搅拌1小时,热过滤,滤饼用热的甲苯淋洗,滤液缓慢降温析出白色固体,过滤,烘干得到(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸74.7g,收率88.3%,HPLC 99.2%。1H-NMR(400MHz,DMSO-d6):10.05(s,1H),7.87-7.83(m,1H),6.79-6.75(m,1H),6.67-6.63(m,1H),3.92(s,3H).
上述为本发明创造的较佳实施例而已,并不用以限制本发明创造,凡在本发明创造的精神和原则之内,所作的任何修改、等同替换等,均应包含在本发明创造的保护范围之内。对于本领域的普通技术人员来说,在不脱离本发明构思的前提下还可以做出若干变形和改进,这些都属于本发明的保护范围,因此本发明专利的保护范围应以所附权利要求为准。
Claims (8)
1.一种(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于,包括如下步骤:
步骤1):糠醛与甲氧胺盐酸盐混合在甲苯中,室温下缓慢加入缚酸剂,随后升温反应得到2-呋喃甲醛O-甲基肟;
步骤2):2-呋喃甲醛O-甲基肟与氰基化试剂在DMSO升温反应得到2-(呋喃-2-基)-2-(甲氧基氨基)乙腈;
步骤3):三氯化铁与甲醇混合,缓慢加入2-(呋喃-2-基)-2-(甲氧基氨基)乙腈与甲醇的混合溶液氧化得到(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物;
步骤4):(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物与硫酸混合,升温水解反应得到(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸。
2.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤1)中,所述缚酸剂选自吡啶或三乙胺。
3.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤1)中,所述糠醛、甲氧胺盐酸盐和缚酸剂摩尔比例为1:1.15-1.20:1.20-1.22。
4.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤2)中,所述氰基化试剂选自***、***或氰基三甲基硅烷。
5.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤2)中,所述选自2-呋喃甲醛O-甲基肟与氰基化试剂摩尔比为1:1.4-1.8。
6.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤3)中,所述2-(呋喃-2-基)-2-(甲氧基氨基)乙腈与三氯化铁摩尔比例为1:2.5-3.0。
7.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤4)中,所述硫酸选自60-65%硫酸水溶液。
8.根据权利要求1所述(Z)-α-(甲氧基亚氨基)呋喃-2-乙酸的制备方法,其特征在于:步骤4)中,所述(Z)-N-甲氧基呋喃-2-酰亚胺基氰化物与硫酸摩尔比例为1:2.2-2.5。
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