CN101863853B - 一锅煮法制备5-羟甲基噻唑工艺 - Google Patents

一锅煮法制备5-羟甲基噻唑工艺 Download PDF

Info

Publication number
CN101863853B
CN101863853B CN 200910251602 CN200910251602A CN101863853B CN 101863853 B CN101863853 B CN 101863853B CN 200910251602 CN200910251602 CN 200910251602 CN 200910251602 A CN200910251602 A CN 200910251602A CN 101863853 B CN101863853 B CN 101863853B
Authority
CN
China
Prior art keywords
hydroxymethylthiazole
chloro
reaction
thiazole
preparing
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN 200910251602
Other languages
English (en)
Other versions
CN101863853A (zh
Inventor
陈小峰
邹春伟
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anhui Baker Pharmaceutical Co.,Ltd.
Original Assignee
ANHUI BIOCHEM UNITED PHARMACEUTICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ANHUI BIOCHEM UNITED PHARMACEUTICAL Co Ltd filed Critical ANHUI BIOCHEM UNITED PHARMACEUTICAL Co Ltd
Priority to CN 200910251602 priority Critical patent/CN101863853B/zh
Publication of CN101863853A publication Critical patent/CN101863853A/zh
Application granted granted Critical
Publication of CN101863853B publication Critical patent/CN101863853B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Thiazole And Isothizaole Compounds (AREA)

Abstract

本发明为一锅煮法制备5-羟甲基噻唑工艺，起始原料2-氯-5-氯甲基噻唑在同一反应器内先后经水解反应和在金属/酸共同作用下发生还原反应最终合成5-羟甲基噻唑。本发明工艺操作简便、安全，成本低廉，可满足大规模生产的要求。

Description

一锅煮法制备5-羟甲基噻唑工艺
技术领域：
本发明属于有机药物合成技术领域，尤其涉及5-羟甲基噻唑的工艺合成技术。
技术背景：
5-羟甲基噻唑，分子式：C4H5NOS，分子量：115
Figure GSB00000229296900011
5-羟甲基噻唑
利托那韦是美国Abbott公司开发的一种HIV蛋白酶抑制剂，单独使用或与洛匹那韦组成复方制剂
Figure GSB00000229296900012
用于治疗艾滋病，是目前艾滋病治疗过程中被广泛采用的二线药物。5-羟甲基噻唑是利托那韦合成过程中所必须的三个中间体之一。
Figure GSB00000229296900013
利托那韦
美国Abbot公司在专利WO9414436如下：
Figure GSB00000229296900014
和US5541206如下：
Figure GSB00000229296900015
中公开了合成5-羟甲基噻唑的噻唑羧酸乙酯还原工艺。但这两种工艺路线都不适合工业化生产5-羟甲基噻唑。
美国专利US6710182公开了一种2-氨基-5-羟甲基噻唑脱氨制备5-羟甲基噻唑的工艺如下：
Figure GSB00000229296900021
丙烯醛用过氧化物合成环氧丙醛，然后和硫脲合成2-氨基-5-羟甲基噻唑，最后脱氨合成5-羟甲基噻唑。
美国Abbott公司在专利US5773625和US5959188如下：
Figure GSB00000229296900022
中公开了一种由2-氯-5-氯甲基噻唑为合成5-羟甲基噻唑的简便方法。2-氯-5-氯甲基噻唑经水解合成2-氯-5-羟甲基噻唑，经催化氢化脱氯合成5-羟甲基噻唑。Abbott公司在专利US5712400如下：
中同样以2-氯-5-氯甲基噻唑为起始原料，在季胺类相转移催化剂催化下与甲酸钠合成2-氯-5-噻唑甲酸甲酯，再经水解合成2-氯-5-氯甲基噻唑，最后催化脱氯合成5-羟甲基噻唑。上述两专利，在还原步骤涉及使用高压反应釜，对批产量大小的产生限制作用，且反应过程易产生催化剂中毒现象。
在专利US5712400的基础上，湖南有色凯铂生物有限公司对以2-氯-5-氯甲基噻唑为起始原料合成5-羟甲基噻唑的工艺进行了改进，并申请专利CN10126100如下：
在该专利中，2-氯-5-氯甲基噻唑与三水合醋酸钠发生亲核取代反应，然后用锌粉在乙醇中还原噻唑甲基乙酸酯，再在氢氧化钠水溶液中水解得到5-羟甲基噻唑，其工艺比较复杂。
发明内容：
为了克服上述技术方案中存在的缺陷，本发明公开一种一锅煮法制备5-羟甲基噻唑新工艺。具体工艺是：所述的的一锅煮法制备5-羟甲基噻唑工艺是将2-氯-5-氯甲基噻唑的水解产物直接在金属/酸的作用下脱氯得到5-羟甲基噻唑。该工艺的关键步骤是2-氯-5-羟甲基噻唑经金属/酸还原合成为5-羟甲基噻唑。专利US5773625和US5959188采用的方法都是加氢加压在Pd/C催化下由2-氯-5-羟甲基噻唑合成5-羟甲基噻唑，此反应要把2-氯-5-羟甲基噻唑从前一步水解反应中分离纯化并达到较高纯度才可进行催化反应，而且反应过程易出现催化剂中毒。中国专利CN10126100中所述的工艺也需要将中间体产物分离出来方可进行下一步反应。
一锅煮法制备5-羟甲基噻唑，其工艺路线是：
Figure GSB00000229296900031
所述的一锅煮法制备5-羟甲基噻唑工艺方法是：水解2-氯-5-氯甲基噻唑得到的2-氯-5-羟甲基噻唑，经金属/酸还原得到目的产物，再经萃取，干燥，过滤，蒸馏得到5-羟甲基噻唑。
所述的一锅煮法制备5-羟甲基噻唑工艺，其特征是，5-羟甲基噻唑合成过程的水解反应和还原反应先后在同一反应器中完成，最终得到5-羟甲基噻唑，避免中间产物2-氯-5羟甲基噻唑的分离过程。
所述的一锅煮法制备5-羟甲基噻唑，其特征是，还原反应过程采用的金属粉可选用：铁粉、锌粉或铝粉；采用的酸可选用：盐酸、硫酸或乙酸，还原反应溶剂可选用水、甲醇或乙醇。
所述的一锅煮法制备5-羟甲基噻唑工艺方法是：若还原过程采用的金属和酸分别为锌粉和浓盐酸，则各原料的重量配比如下：
2-氯-5-氯甲基噻唑                  100
锌粉                               40-60
浓盐酸                             20-40
水                                 1000
乙酸乙酯                     900-1200
无水硫酸钠                   40-60
本发明的最大特点是5-羟甲基噻唑采用一锅煮法制备，即该工艺的水解、还原等两步反应在同一反应器中即可先后完成，且所得产物具有较高纯度，可达到直接用于利托那韦合成的要求。本发明工艺还具有合成方法简单、易于操作、原材料易于采购等特点，可有效降低5-羟甲基噻唑的成本，具有较高的工业应用价值。
具体实施方式：
实例1：
于250ml烧瓶中加入5g 2-氯-5-氯甲基噻唑和50g H2O，80℃下加热搅拌反应2hr，加入2.5g锌粉，缓慢滴加1.3g浓盐酸。加毕，继续搅拌反应30min，冷至室温，过滤除去过量的锌粉。滤液减压浓缩至原体积的1/5，用饱和NaHCO3水溶液调pH约为9，过滤，滤饼用10ml乙酸乙酯洗一次，滤液用乙酸乙酯250ml萃取。合并萃取液以及清洗滤饼的乙酸乙酯，加入2.5g无水Na2SO4干燥后过滤，减压除溶剂后得浅黄色油状物2.6g，收率68％，纯度＞98％。
实例2：
于5L烧瓶中加入300g 2-氯-5-氯甲基噻唑和3.0L水，80℃下加热搅拌反应2hr，加入150.0g锌粉，缓慢滴加75ml浓盐酸。加毕，继续搅拌反应30min，冷至室温，过滤除去过量的锌粉。滤液减压浓缩至原体积的1/5，用饱和NaHCO3水溶液调pH约为9，过滤，滤饼用600ml乙酸乙酯洗一次，滤液采用3L乙酸乙酯萃取。合并萃取液以及清洗滤饼的乙酸乙酯，加入150g无水Na2SO4干燥后过滤，减压除溶剂后得浅黄色油状物152g，收率66％，纯度＞98％。
实例3：
于1500L反应釜中加入90kg 2-氯-5-氯甲基噻唑和900kg水，升温至80℃搅拌反应2hr，加入45kg锌粉，缓慢滴加27kg浓盐酸。加毕，继续搅拌反应30min，冷至室温，过滤除去过量的锌粉。滤液减压蒸出水约700kg，用饱和NaHCO3水溶液调pH约为9，过滤，滤饼用162kg乙酸乙酯洗一次，滤液采用810kg乙酸乙酯萃取。合并萃取液以及清洗滤饼的乙酸乙酯，加入45kg无水Na2SO4干燥后过滤，减压除溶剂后得浅黄色油状物48kg，收率69％，纯度＞98％。

Claims (1)

1.一锅煮法制备5-羟甲基噻唑的工艺方法，是：
将2-氯-5-氯甲基噻唑与水进行水解反应，得到2-氯-5-羟甲基噻唑；
将所述2-氯-5-羟甲基噻唑经锌/盐酸还原，再萃取，干燥，过滤，蒸馏得到5-羟甲基噻唑，
5-羟甲基噻唑合成过程的水解反应和还原反应先后在同一反应器中完成，最终得到5-羟甲基噻唑，避免中间产物2-氯-5-羟甲基噻唑的分离过程。
CN 200910251602 2009-12-28 2009-12-28 一锅煮法制备5-羟甲基噻唑工艺 Active CN101863853B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 200910251602 CN101863853B (zh) 2009-12-28 2009-12-28 一锅煮法制备5-羟甲基噻唑工艺

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 200910251602 CN101863853B (zh) 2009-12-28 2009-12-28 一锅煮法制备5-羟甲基噻唑工艺

Publications (2)

Publication Number Publication Date
CN101863853A CN101863853A (zh) 2010-10-20
CN101863853B true CN101863853B (zh) 2012-12-19

Family

ID=42955815

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200910251602 Active CN101863853B (zh) 2009-12-28 2009-12-28 一锅煮法制备5-羟甲基噻唑工艺

Country Status (1)

Country Link
CN (1) CN101863853B (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104693140B (zh) * 2015-02-13 2016-08-31 江苏森萱医药化工股份有限公司 一种5-羟甲基噻唑纯化工艺
CN111548321A (zh) * 2020-04-13 2020-08-18 南通森萱药业有限公司 一种利托那韦中间体5-羟甲基噻唑的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5712400A (en) * 1994-11-22 1998-01-27 Abbott Laboratories Process for preparation of 5-hydroxymethylthiazole
US5773625A (en) * 1997-10-02 1998-06-30 Abbott Laboratories Process for the preparation of disubstituted carbonates
US5959118A (en) * 1997-08-29 1999-09-28 Abbott Laboratories Process for the preparation of 5-hydroxymethylthiazoles
CN101260100A (zh) * 2008-04-21 2008-09-10 湖南有色凯铂生物药业有限公司 一种5-羟甲基噻唑的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5712400A (en) * 1994-11-22 1998-01-27 Abbott Laboratories Process for preparation of 5-hydroxymethylthiazole
US5959118A (en) * 1997-08-29 1999-09-28 Abbott Laboratories Process for the preparation of 5-hydroxymethylthiazoles
US5773625A (en) * 1997-10-02 1998-06-30 Abbott Laboratories Process for the preparation of disubstituted carbonates
CN101260100A (zh) * 2008-04-21 2008-09-10 湖南有色凯铂生物药业有限公司 一种5-羟甲基噻唑的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
李青 等.5-羟甲基噻唑的合成.《化学试剂》.2008,第30卷(第11期), *
殷作虎 等.5-羟甲基噻唑合成工艺的研究进展.《精细化工中间体》.2008,第38卷(第3期), *

Also Published As

Publication number Publication date
CN101863853A (zh) 2010-10-20

Similar Documents

Publication Publication Date Title
US20160228859A1 (en) Use of certain organic materials, containing alkali or alkaline-earth metals, for implementing organic chemical reactions
CN103319414A (zh) 替米沙坦制备工艺的改进
CN102229581B (zh) 非布司他中间体的制备方法
CN101863853B (zh) 一锅煮法制备5-羟甲基噻唑工艺
CN105294534A (zh) 制备阿普司特及其中间体的产业化方法
CN103319389A (zh) 一种由万寿菊浸膏制备食品级叶黄素晶体的方法
CN101870682B (zh) 4-甲基噻唑醛-5的制备方法
CN101407513A (zh) 一种核苷类似物的合成方法
CN102442972B (zh) 一种普拉克索及其二盐酸盐一水合物的工业化制备方法
CN103554206A (zh) 一种从猪胆汁中分离猪胆酸的方法
CN103664923A (zh) 硝呋太尔的制备方法
CN102417472A (zh) 一种氟苯尼考的制备方法
CN113181967A (zh) 磺酸化钛改性的kit-6固体酸催化剂在合成龙脑中的应用
CN104610261A (zh) 更昔洛韦中间体的制备方法
CN104478972B (zh) 一种采用自吸式搅拌高压釜制备曲克芦丁的方法
CN102180864B (zh) 一种雷尼酸锶的制备方法
CN103539829A (zh) 一种熊去氧胆酸的提取方法
CN101607950B (zh) 制备5-氨基苯并呋喃羧酸酯的方法
CN103539828A (zh) 从去除胆红素的猪胆汁下脚料中提取猪去氧胆酸的方法
CN107200763A (zh) 一种以鹅去氧胆酸为原料合成石胆酸的方法
CN105254611A (zh) 苯并噻吩-2-羧酸的制备方法
CN103145692B (zh) 一种4,5-二氢-6H-环戊烷并[b]噻吩-6-酮的制备方法
CN102464699A (zh) 一种甘珀酸钠的制备方法
CN103755727B (zh) 布林佐胺中间体制备方法
CN1122016C (zh) 树脂催化合成乙酸叶酯

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
EE01 Entry into force of recordation of patent licensing contract

Application publication date: 20101020

Assignee: Beijing is standing grain profit and Pharmaceutical Technology Co., Ltd too

Assignor: Anhui Biochem United Pharmaceutical Co., Ltd.

Contract record no.: 2013990000727

Denomination of invention: Technique for preparing 5-hydroxymethyl thiazole by one pot method

Granted publication date: 20121219

License type: Exclusive License

Record date: 20131031

LICC Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Technique for preparing 5-hydroxymethyl thiazole by one pot method

Effective date of registration: 20150428

Granted publication date: 20121219

Pledgee: Agricultural Bank of China, Taihe County, Limited by Share Ltd branch

Pledgor: Anhui Beck United Pharmaceutical Co., Ltd.|Anhui Beck Biological Pharmaceutical Co., Ltd.

Registration number: 2015990000330

PLDC Enforcement, change and cancellation of contracts on pledge of patent right or utility model
EC01 Cancellation of recordation of patent licensing contract

Assignee: Beijing is standing grain profit and Pharmaceutical Technology Co., Ltd too

Assignor: Anhui Biochem United Pharmaceutical Co., Ltd.

Contract record no.: 2013990000727

Date of cancellation: 20151023

LICC Enforcement, change and cancellation of record of contracts on the licence for exploitation of a patent or utility model
PC01 Cancellation of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20180522

Granted publication date: 20121219

Pledgee: Agricultural Bank of China, Taihe County, Limited by Share Ltd branch

Pledgor: Anhui Biochem United Pharmaceutical Co., Ltd.|Anhui Biochem Bio-Pharmaceutical Co., Ltd.

Registration number: 2015990000330

PE01 Entry into force of the registration of the contract for pledge of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: Technique for preparing 5-hydroxymethyl thiazole by one pot method

Effective date of registration: 20180523

Granted publication date: 20121219

Pledgee: Agricultural Bank of China, Taihe County, Limited by Share Ltd branch

Pledgor: Anhui Biochem United Pharmaceutical Co., Ltd.|Anhui Biochem Bio-Pharmaceutical Co., Ltd.

Registration number: 2018340000175

PC01 Cancellation of the registration of the contract for pledge of patent right
PC01 Cancellation of the registration of the contract for pledge of patent right

Date of cancellation: 20210618

Granted publication date: 20121219

Pledgee: Agricultural Bank of China Taihe County Limited by Share Ltd. branch

Pledgor: ANHUI BIOCHEM UNITED PHARMACEUTICAL Co.,Ltd.

Registration number: 2018340000175

PE01 Entry into force of the registration of the contract for pledge of patent right
PE01 Entry into force of the registration of the contract for pledge of patent right

Denomination of invention: One pot preparation of 5-hydroxymethylthiazole

Effective date of registration: 20210629

Granted publication date: 20121219

Pledgee: Agricultural Bank of China Taihe County Limited by Share Ltd. branch

Pledgor: ANHUI BIOCHEM UNITED PHARMACEUTICAL Co.,Ltd.

Registration number: Y2021340000011

CP01 Change in the name or title of a patent holder
CP01 Change in the name or title of a patent holder

Address after: 236604 No. 108, middle Shahe Road, Taihe County, Anhui Province

Patentee after: Anhui Baker Pharmaceutical Co.,Ltd.

Address before: 236604 No. 108, middle Shahe Road, Taihe County, Anhui Province

Patentee before: ANHUI BIOCHEM UNITED PHARMACEUTICAL Co.,Ltd.