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【结 构 式】

【药物名称】Cefdinir, PD-134393, CI-983, FR-80482, FK-482, Omnicef, Cefzon

【化学名称】(6R,7R)-7-[2-(2-Aminothiazol-4-yl)-2(Z)-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid

【CA登记号】91832-40-5

【 分 子 式 】C14H13N5O5S2

【 分 子 量 】395.41821

【开发单位】Fujisawa (Originator), Abbott (Licensee)

【药理作用】Antibiotics, ANTIINFECTIVE THERAPY, Cephalosporins

合成路线1

 

1 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982.
2 胡艾希,徐娟娟,伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229
3 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480
4 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007.
5 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743.
6 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738.
7 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995.
8 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001.
9 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989.
10 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997.
11 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22747 (6R,7R)-3-[(acetoxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C10H12N2O5S 详情 详情
(II) 69618 (6R,7R)-7-amino-3-(hydroxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C8H10N2O4S 详情 详情
(III) 21351 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde 90-02-8 C7H6O2 详情 详情
(VIII) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(IX) 69619 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate C31H22N4O2S3 详情 详情

合成路线2

 

1 Huwiler A,Teund L.Production of 2-(2-aminothiazole-4-yl)-2- (syn)-methoxyimino acetic esters:EP,Patent 45,005,1982.
2 胡艾希,徐娟娟,伍小云.氨噻肟酸乙酯的合成.中国医药工业杂 志.2206,37.229
3 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480
4 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007.
5 Defossa E,Fischer G,Gerlach U,et al.Synthesis of HR 916 K.Am efficient route to the pure diastereomers of the 1-(pivaloyloxy)ethyl esters of cephalosporins.Liebigs Annalen,1996,(11):1743.
6 Yamanaka H,Chiba T,Kawabata K,et al.Studies on β-lactam antibiotics.IX.Synthesis and biological activity of new orally active cephalosporin,cefixime(FK027).J Antibiotics,1985,38:1738.
7 Takaya T,Takasugi H,Masugi T,et al.7-Acylamino-3-substituted cephalosporanic acid derivatives,processes for their preparation and pharmaceutical compositions containing them:EP,Patent 29,557,1995.
8 Kameyama Y,Fukae K.Method for producing 3-vinyl-cephem compound:JP,Patent 2,001,294,590,2001.
9 Takaya T,Shirai F,Nakamura H,et al.Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer):EP,Patent 304,019,1989.
10 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997.
11 Sturm H,Wolf S,Ludescher J.Crystalline amine salt of cefdinir:WO,Patent 9,845,299,1998.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23541 ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(II) 39961 ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate C6H8ClNO4 详情 详情
(III) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情
(IV) 48461 (Z)-ethyl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate;ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetate C26H23N3O3S 详情 详情
(V) 48462 2-(2-amino-1,3-thiazol-4-yl)-2-[(trityloxy)imino]acetic acid;(Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetic acid 128438-01-7 C24H19N3O3S 详情 详情
(VI) 69620 1-(2,5-dimethoxyphenyl)propan-2-amine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate C24H19N3O3S.C11H17NO2 详情 详情
(VII) 69619 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate C31H22N4O2S3 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线3

 

1 程清蓉,刘志雄,李翔,等.去甲氨噻肟酸乙酯的合成研究.化学世界,2007,48:480
2 郑庚修,李贺,赵叶青.制备去甲氨噻肟酸乙酯的方法:CN,Patent 101,007,793,2007.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23541 ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloro-3-oxobutanoate;Ethyl 4-chloroacetoacetate 638-07-3 C6H9ClO3 详情 详情
(II) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(III) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线4

 

1 Gonzalez M,Rodriguez Z,Tolon B,et al.An alternative procedure for preparation of cedinir.Farmaco,2003,58:409.
2 朱阳,刘国庆,陆建中,等.(Z)-2-(2-氨基噻唑-4-基)-2-三苯甲氧基亚氨基乙酸合成的改进.中国医药工业杂志,1997,28:27.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 20853 ethyl 2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 2-(hydroxyimino)-3-oxobutanoate C6H9NO4 详情 详情
(III) 39961 ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate;(Z)-ethyl 4-chloro-2-(hydroxyimino)-3-oxobutanoate C6H8ClNO4 详情 详情
(IV) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(V) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线5

 

1 任红阳,厉昆,陈亮.制备(Z)-2-(2-氨基-4-噻唑)-2-羟基亚胺乙酸酯及其衍生物的方法:CN,Patent 1,709,879,2005.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69621 (Z)-ethyl 2-(hydroxymethylene)-3-oxobutanoate C7H10O4 详情 详情
(II) 69622 (Z)-ethyl 4-chloro-2-(hydroxymethylene)-3-oxobutanoate C7H9ClO4 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线6

 

1 宫平,宫凤仙,王钝.2-(2-氨基-噻唑)-(Z)-羟基亚胺基乙酸乙酯的合成.沈阳药科大学学报,1998,15:235.
2 Arita H,Ikeda K,Akamatsu H.Production of (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetic acid ester:JP,Patent 09,194,470 1997.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11819 ethyl acetoacetate; ethyl 3-oxobutanoate;Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate 141-97-9 C6H10O3 详情 详情
(II) 36651 Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate 13176-46-0 C6H9BrO3 详情 详情
(III) 10180 Thiourea 62-56-6 CH4N2S 详情 详情
(IV) 15889 Ethyl 2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate;(Z)-ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate; ethyl 2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetate 60845-81-0 C7H9N3O3S 详情 详情

合成路线7

 

1 Cabri W,Alpegiani M,Pozzi G,et al.A process for the preparation of cephalosporins side chain:WO,Patent 2.003,040,116,2003.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 10183 (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetic acid;2-(2-Amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetic acid 66338-96-3 C5H5N3O3S 详情 详情
(II) 69623 triethylamine (Z)-2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetate C24H19N3O3S.C6H15N 详情 详情
(III) 69619 (Z)-S-benzo[d]thiazol-2-yl 2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)ethanethioate C31H22N4O2S3 详情 详情

合成路线8

 

1 Gonzalez M,Rodriguez Z,Tolon B,et al.An alternative procedure for preparation of cedinir.Farmaco,2003,58:409.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成

合成路线9

 

1 Singh GP,Sen H,Srivastava D,et al.Stable bioavailable crystalline form or cefdinir and a process for the preparation thereof:US,Patent 2,005,245,738,2005.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69624 sodium (Z)-2-(2-(tritylamino)thiazol-4-yl)-2-((trityloxy)imino)acetate C43H32N3NaO3S 详情 详情
(II) 69625 (6R,7R)-4-methoxybenzyl 7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C17H18N2O4S 详情 详情

合成路线10

 

1 Dandala R,Prasada Rao KVV,Sivakumaran MS.Process for preparaing cefinir:US,Patent 2,004,242,557,2004.
2 Prasada Rao KVV,Dandala R,Sivakumaran M,et al.Improved synthesis of Cefdinir and its polymorphic form,an antibacterial active pharmaceutical ingredient.Synthetic Commun,2007,37:2275.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69626 (Z)-S-benzo[d]thiazol-2-yl 2-(acetoxyimino)-2-(2-aminothiazol-4-yl)ethanethioate C14H10N4O3S3 详情 详情
(II) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线11

 

1 Deshpande PB,Khadangale BP,Ramasubbu C.Novel amorphous hydrate of a cephalosporin antibiotic:WO,Patent 2,004,046,154,2004.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69627 (Z)-S-(5-phenyl-1,3,4-oxadiazol-2-yl) 2-(acetoxyimino)-2-(2-aminothiazol-4-yl)ethanethioate C15H11N5O4S2 详情 详情
(II) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线12

 

1 Lee GS,Chang YK,Chun JP,et al.Process for preparation of cefdinir:WO,Patent 9,724,358,1997.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69628 (Z)-(2-(2-aminothiazol-4-yl)-2-((trityloxy)imino)acetoxy)(1,3-diethyltrioxidan-2-iumyl)phosphanide C28H28N3O6PS 详情 详情
(II) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线13

 

1 Kremminger P,Silberberger H.Tertiary amine salts of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid:WO,Patent 2,006,008,160,2006.
2 Kremminger P,Silberberger H.Alkanoyl amide solvates of 2-(2-aminothiazole-4-yl)-2-(acyloxyimino)acetic acid:WO,Patent 2,006,008,161,2006.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69626 (Z)-S-benzo[d]thiazol-2-yl 2-(acetoxyimino)-2-(2-aminothiazol-4-yl)ethanethioate C14H10N4O3S3 详情 详情
(II) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情

合成路线14

 

1 Server NE,Law D.Stable amorphous cefdinir:WO,Patent 2,005,100,368,2005.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成

合成路线15

 

1 Datta D,Dantu M,Mishra B,et al.Novel intermediates for synthesis of cephalosporins and process for preparation of such intermediates:WO,Patent 2,004,058,695,2004.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 58114 4-bromo-2-(methoxyimino)-3-oxobutanoic acid;(Z)-4-bromo-2-(methoxyimino)-3-oxobutanoic acid C5H6BrNO4 详情 详情
(II) 69629   C3H7Cl2NO3S 详情 详情
(III) 69630   C8H12BrClN2O6S 详情 详情
(IV) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(V) 69631 (6R,7R)-7-((Z)-4-bromo-2-(methoxyimino)-3-oxobutanamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C14H14BrN3O6S 详情 详情
(VI) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线16

 

1 Sakane K,Goto J.Production of 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamide)-3-cephem compound:JP,Patent 02,000,790,1990.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 69632 (Z)-2-(acetoxyimino)-2-(2-aminothiazol-4-yl)acetyl chloride C7H6ClN3O3S 详情 详情
(II) 69633 (E)-trimethylsilyl N-(trimethylsilyl)acetimidate;N,O-Bis(trimethylsilyl)acetamide;Trimethylsilyl N-trimethylsilylacetamidate; 10416-59-8 C8H21NOSi2 详情 详情
(III) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(IV) 69634 (6R,7R)-7-((Z)-2-(acetoxyimino)-2-(2-aminothiazol-4-yl)acetamido)-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic aci C16H15N5O6S2 详情 详情

合成路线17

The condensation of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate (I) with 4-bromoacetoacetyl bromide (II) by means of trimethylsilylacetamide in ethyl acetate gives benzhydryl 7-(4-bromoaceto-acetamido)-3-vinyl-3-cephem-4-carboxylate (III), which by reaction with NaNO2 - acetic acid in dichloromethane and then with urea is converted to benzhydryl 7-[4-bromo-2-(hydroxyimino)acetoacetamido]-3-vinyl-3-cephem-4 carboxylate (IV). The cyclization of (IV) with thiourea in dimethylacetamide affords benzhydryl 7-[2-(2-aminothiazol-4-yl) (hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (V), which is finally hydrolyzed with trifluoroacetic acid - anisole as usual.

1 Kawabata, K.; Masugi, T.; Takaya, T.; Taksugi, H.; Yamanaka, H. (Fujisawa Pharmaceutical Co., Ltd.); Syn-isomer of 7-substd.-3-vinyl-3-cephem cpds., pr. EP 0105459; ES 8600309; ES 8800235; US 4559334 .
2 Castaner, J.; Prous, J.; FK-482. Drugs Fut 1988, 13, 3, 224.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 22001 benzhydryl (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C22H20N2O3S 详情 详情
(II) 15619 5-(acetoxy)-1,3-oxathiolane-2-carboxylic acid C6H8O5S 详情 详情
(III) 22003 benzhydryl (6R,7R)-7-[(4-bromo-3-oxobutanoyl)amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C26H23BrN2O5S 详情 详情
(IV) 22004 benzhydryl (6R,7R)-7-[[4-bromo-2-(hydroxyimino)-3-oxobutanoyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C26H22BrN3O6S 详情 详情
(V) 22005 benzhydryl (6R,7R)-7-[[2-(2-amino-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino]-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate C27H23N5O5S2 详情 详情
(VI) 63021 N-(trimethylsilyl)acetamide 13435-12-6 C5H13NOSi 详情 详情
(VII) 19310 urea 57-13-6 CH4N2O 详情 详情
(VIII) 10180 Thiourea 62-56-6 CH4N2S 详情 详情

合成路线18

The condensation of 2-(2-aminothiazol-4-yl)-2(Z)-(trityoloxyimino)thioacetic acid 2-benzothiazolyl ester (I) with 7-amino-3-vinyl-3-cephem-4-carboxylic acid (II) by means of tributylamine in DMA gives the corresponding amide (III), which is deprotected by means of HCl and formic acid to provide cefdinir.

1 Singh, S.K.; Kumar, Y.; Prasad, M.; Prasad, A.; Kumar, N.P. (Ranbaxy Laboratories Ltd.); Process for the preparation of cefdinir. WO 0391261 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 64881 S-(1,3-benzothiazol-2-yl) 2-(2-amino-1,3-thiazol-4-yl)-2-{[(triphenylmethyl)oxy]imino}ethanethioate C31H22N4O2S3 详情 详情
(II) 64882 (6R,7R)-7-amino-8-oxo-3-vinyl-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 79349-82-9 C9H10N2O3S 详情 详情
(III) 64883 7-[(2-(2-amino-1,3-thiazol-4-yl)-2-{[(triphenylmethyl)oxy]imino}acetyl)amino]-3-ethenyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid C33H27N5O5S2 详情 详情

合成路线19

 

1 Inamoto Y,Chiba T,Kaminura T,et al.FK 482,a new orally active cephalosporin.Synthesis and biological properties.J Antibiotics,1988,41:828.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
Extended Information