制藥工程 專(zhuān)業(yè)英語(yǔ) Unit

《制藥工程 專(zhuān)業(yè)英語(yǔ) Unit》由會(huì)員分享，可在線閱讀，更多相關(guān)《制藥工程 專(zhuān)業(yè)英語(yǔ) Unit（81頁(yè)珍藏版）》請(qǐng)?jiān)谘b配圖網(wǎng)上搜索。

1、會(huì)計(jì)學(xué)1制藥工程制藥工程 專(zhuān)業(yè)英語(yǔ)專(zhuān)業(yè)英語(yǔ) Unit 第1頁(yè)/共81頁(yè)第2頁(yè)/共81頁(yè)第3頁(yè)/共81頁(yè)第4頁(yè)/共81頁(yè)第5頁(yè)/共81頁(yè)nDiscuss some topics.第6頁(yè)/共81頁(yè)第7頁(yè)/共81頁(yè)第8頁(yè)/共81頁(yè)藥品的生產(chǎn)依據(jù)其生產(chǎn)或來(lái)源，藥物制劑可以分為三類(lèi)：I.完全的合成材料（人工合成材料），II.天然產(chǎn)物，和III.源自部分合成的產(chǎn)品（半合成產(chǎn)品）。 Depending on their production or origin pharmaceutical agents can be split into three groups:I . Totally synthetic

2、 materials (synthetics)，II. Natural products，andIII. Products from partial syntheses (semi-synthetic products).第9頁(yè)/共81頁(yè)n. 用作復(fù)人工合成(絕緣)材料n. 配醣；配糖體；糖苷n. 水解液；水解產(chǎn)物n. 葡萄聚糖；右旋糖酐定向（或靶向）修飾n. 腎上腺素n. 藥 左旋多巴（等于L-dopa）n. 前列腺素（prostaglandin的復(fù)數(shù)形式）n. D-青霉胺n. 長(zhǎng)春胺n. 真核細(xì)胞n. 原核細(xì)胞腸膜狀明串珠菌谷氨酸棒桿菌黃色短桿菌謝氏丙酸桿菌嘌呤核苷（酸）檸檬酸谷氨酸鈉（味

3、精）n. 核染色質(zhì)；核染質(zhì)第10頁(yè)/共81頁(yè)第11頁(yè)/共81頁(yè) 本書(shū)的重點(diǎn)是在于和類(lèi)中最重要的化合物藥物合成。但是，這并不意味著，天然產(chǎn)品或其他制劑并不太重要。它們可以作為有價(jià)值的先導(dǎo)結(jié)構(gòu)，他們常常作為重要的合成產(chǎn)品的起始原料或中間體產(chǎn)品。 表1列出了獲取藥物制劑的不同方法的概述。 The emphasis of the present book is on the most important compounds of groups I and - thus Drug synthesis. This does not mean，however，that natural products or

4、 other agents are less important. They can serve as valuable lead structures，and they are frequently needed as starting materials or as intermediates for important synthetic products. Table 1 gives an overview of the different methods for obtaining pharmaceutical agents.第12頁(yè)/共81頁(yè) 最初從天然資源庫(kù)獲得的幾個(gè)重要治療作用

5、的天然產(chǎn)品，今天可以通過(guò)全合成更有效地，例如更經(jīng)濟(jì)地被制備出來(lái)。這樣的例子包括L-氨基酸、氯霉素、咖啡因、多巴胺、腎上腺素、左旋多巴、肽類(lèi)激素、前列腺素、D -青霉胺、長(zhǎng)春胺，以及幾乎所有的維生素。 Several therapeutically significant natural products which were originally obtained from natural sources are today more effectively -i. e. more economically -prepared by total synthesis. Such examples

6、 include L-amino acids, Chloramphenicol, Caffeine, Dopamine, Epinephrine, Levodopa, peptide hormones, Prostaglandins, D-Penicillamine, Vincamine, and practically all vitamins.第13頁(yè)/共81頁(yè) 在過(guò)去的幾年里，發(fā)酵，即微生物過(guò)程，變得極其重要。通過(guò)現(xiàn)代技術(shù)和基因選擇導(dǎo)致的微生物的高性能突異變種的結(jié)果，發(fā)酵已成為選擇寬范圍物質(zhì)的方法。真核細(xì)胞（酵母菌和霉菌）和原核細(xì)胞（單細(xì)胞細(xì)菌，放線菌）都可用作微生物?？梢缘玫较铝挟a(chǎn)品類(lèi)

7、型： Over the last few years fermentation - i. e. microbiological processes has become extremely important. Through modern technology and results from genetic selection leading to the creation of high performance mutants of microorganisms, fermentation has already become the method of choice for a wid

8、e range of substances. Both Eukaryonts (yeasts and moulds)and Prokaryonts(single bacterial cells, and actinomycetes)are used microorganisms. The following product types can be obtained: 第14頁(yè)/共81頁(yè) 盡管從諸如腸膜狀明串球菌的某些微生物的黏膜可以生產(chǎn)葡萄聚糖，但第2和3類(lèi)產(chǎn)品類(lèi)型只與藥品生產(chǎn)的有關(guān)。葡聚糖自身的分子量5萬(wàn)10萬(wàn)，可用作血漿代用品。而來(lái)自谷氨酸棒桿菌和黃色短桿菌突變體的初級(jí)代謝產(chǎn)物中，L-氨

9、基酸尤其令人感興趣。從這些生物體中，可以生產(chǎn)約35萬(wàn)噸L-谷氨酸單鈉鹽（味精，食品添加劑）和約70,000噸L-賴(lài)氨酸（用于植物蛋白補(bǔ)充物質(zhì)）。此外，重要的初級(jí)代謝產(chǎn)物還有嘌呤核苷酸、有機(jī)酸、乳酸、檸檬酸和維生素，例如源自謝氏丙酸桿菌的維生素B12。 Disregarding the production of dextran from the mucous membranes of certain microorganisms，e. g. Leuconostoc mesenteroides, classes 2 and 3 are the relevant ones for the prep

10、aration of drugs. Dextran itself, with a molecular weight of 50,000 100,000, is used as a blood plasma substitute. Among the primary metabolites the L-amino acids from mutants of Corynebacterium glutamicum and Brevibacterium flavum are especially interesting. From these organisms some 350,000 tones

11、of monosodium L-glutamate (food additive) and some 70,000 tones of L-lysine (supplement for vegetable proteins) are produced. Further important primary metabolites are the purina nucleotides, organic acids, lactic acid, citric acid, and vitamins, for example vitamin B12 from Propionibacterium sherma

12、nii.第15頁(yè)/共81頁(yè) 在次生代謝產(chǎn)物中首先必須提到的是抗生素。以下五組藥品代表了全球每年價(jià)值170億美元： 青霉素類(lèi)（產(chǎn)黃青霉）， 頭孢菌素類(lèi)（頂頭孢霉菌）， 四環(huán)素類(lèi)（金霉素鏈霉菌）， 紅霉素類(lèi)（紅霉素鏈霉菌）， 氨基糖苷（如來(lái)自灰色鏈霉菌的鏈霉素）。 Among the secondary metabolites the antibiotics must be mentioned first. The following five groups represent a yearly worldwide value of US-$17 billion: penicillins ( Pe

13、nicillium chrysogenum )， cephalosporins ( Cephalosporium acremonium )， tetracyclines ( Streptomyces aureofaciens )， erythromycins ( Streptomyces erythreus )， aminoglycosides (e. g. streptomycin from Streptomyces griseus).第16頁(yè)/共81頁(yè) Dextran is a polymer of glucose. It is a white powder and it is solub

14、le in water and insoluble in ethanol. Dextran can increase the plasma volume and maintain the blood pressure, so it can be used for as a blood plasma substitute. It can be produced by fermentation of sucrose in leuconostoc mesenteroides. Certainly, the fermentation only produce the raw material and

15、the some purification is necessary. glucose 葡萄糖葡萄糖fructose 果糖果糖 OOOmono-, di-, tri-, polymer單體，二聚體，三聚體，聚合體(物)sucrose n.蔗糖第17頁(yè)/共81頁(yè) 從微生物中已分離出約5000種抗生素，但其中只有不到100種有治療用途。但是，必須記住，許多衍生物已通過(guò)部分合成法來(lái)修飾以獲得治療用途；在過(guò)去的十年里，采用半合成方法已從-內(nèi)酰胺獲得了約50,000種制劑。發(fā)酵是在體積高達(dá)400m3的不銹鋼發(fā)酵罐中進(jìn)行。為了避免受到噬菌體等微生物的污染，（發(fā)酵）全過(guò)程都必須在無(wú)菌條件下進(jìn)行。由于更重要的

16、是，發(fā)酵只在有氧條件下才能發(fā)生；因此，需要提供有足夠量的（無(wú)菌）氧氣或空氣。二氧化碳的來(lái)源包括糖類(lèi)（碳水化合物），如廢糖漿、低聚糖類(lèi)和葡萄糖。 About 5000 antibiotics have already been isolated from microorganisms, but of these only somewhat fewer than 100 are in therapeutic use. It must be remembered，however，that many derivatives have been modified by partial synthesis

17、 for therapeutic use; some 50,000 agents have been semisynthetically obtained from -lactams alone in the last decade. Fermentations are carried out in stainless steel fermentors with volumes up to 400 m3. To avoid contamination of the microorganisms with phages etc. the whole process has to be perfo

18、rmed under sterile conditions. Since the more important fermentations occur exclusively under aerobic conditions, a good supply of oxygen or air (sterile) is needed. Carbon dioxide sources include carbohydrates, e. g. molasses, saccharides, and glucose. 第18頁(yè)/共81頁(yè)銨；銨鹽 （氨；氨水） 胺碳酸氫鈉；小蘇打、 NaHCO3氫氧化鈉 、Na

19、OH鹽酸；硫酸；硝酸次氯酸鹽（酯）亞氯酸鹽（酯）氯酸鹽（酯）高氯酸鹽（酯）亞硝酸鹽（酯）硝酸鹽（酯）硫化物；硫醚亞硫酸鹽（酯）硫酸鹽（酯）過(guò)硫酸鹽（酯）亞磷酸鹽（酯）次磷酸鹽（酯）磷酸鹽（酯）磷酸二氫鹽磷酸一氫鹽第19頁(yè)/共81頁(yè)Nomenclature of Organic Compounds 1第20頁(yè)/共81頁(yè)第21頁(yè)/共81頁(yè)第22頁(yè)/共81頁(yè)CH3CH2CCH2CH2CH3CH2CH3CH3第23頁(yè)/共81頁(yè)CH3CHCH2CH2 CH2CHCH3CH2CH3CH3CH3CH2CHCH2 CH2CH3CHCH3CH3第24頁(yè)/共81頁(yè)CH3(CH2)3CH3CH3CCH3CH3CH3

20、CH3CHCH3CH3CH3CCH3OHCH3CH3CHCH2NH2CH3CH3CH2CHNH2CH3第25頁(yè)/共81頁(yè)CHCHCH3CH3CHCHCH2CHCCHCCH2第26頁(yè)/共81頁(yè)CHCHCH2CH2CH2CCH2CH2CHCH2CHCH2CH3CCH2第27頁(yè)/共81頁(yè)CH2CCH2CHCHCH3CH3第28頁(yè)/共81頁(yè)CH3CH3CH3CHCH2CH3CH3CH3CH3CH3CH3CH3CH3CHCH2CH3CH3CH3CH3CH3CH2第29頁(yè)/共81頁(yè)CH3CH3CH3CH2CHCH2CH3CH3CH3CH3CH2CH3第30頁(yè)/共81頁(yè)第31頁(yè)/共81頁(yè)第32頁(yè)/共81頁(yè)C

21、H3CH2BrCH3CHCH3BrCH3CBrCH3CH3a primary alkyl halidea secondary alkyl halide a tertiary alkyl halide ethyl bromide tert-butyl bromide sec-propyl bromide第33頁(yè)/共81頁(yè)CH3CH2ClCH3CHCH3FCH3CBrCH3CH3 sec-propyl fluoride ethyl chloride tert-butyl bromideCH3I methyl iodide 2-fluoropropane chloroethane2-bromo-2-

22、methylpropane iodomethane第34頁(yè)/共81頁(yè)CH3CH2OHCH3CHCH3OHCH3COHCH3CH3sec-propyl alcohol (isopropyl alcohol) ethyl alcoholtert-butyl alcohol2-propanol ethanol2-methyl2-propanolNomenclature of alcohols第35頁(yè)/共81頁(yè)RNH2a secondary amine a primary aminea tertiary amineRNHRRNRRRCRRNH2RCRROH a primary amine a tert

23、iary alcoholNomenclature of amines第36頁(yè)/共81頁(yè)CH3NCH3CH3CH3NCH2CH2CH2CH3CH2CH3CH3NCH2CH3CHCH2CH2CH3CH2Cltrimethylaminebutylethylmethylamineno common name第37頁(yè)/共81頁(yè)第38頁(yè)/共81頁(yè)CH3NCH3CH3CH3NCH2CH2CH2CH3CH2CH3CH3NCH2CH3CHCH2CH2CH3CH2Cldimethylaminomethane1-(ethylmethylamino)butane1-chloro-2-(ethylmethylamino

24、)pentaneorN,N-dimethylmethanamineorN-ethyl-N-methylbutanamineor1-chloro-N-ethyl-N-methyl-2-pentanaminetrimethylaminebutylethylmethylamineno common name第39頁(yè)/共81頁(yè)CH3N+CH3CH3CH3CH3N+CH2CH2CH2CH3CH2CH3CH3CH3N+CH2CH3CHCH2CH2CH3CH2ClCH3OH-Cl-Br-tetramethylammonium hydroxide(1-chloromethyl)butylethyldimeth

25、ylammonium bromidebutylethyldimethylammoniumchloride第40頁(yè)/共81頁(yè)RORRORa symmetrical etheran asymmetrical ether第41頁(yè)/共81頁(yè)CH3OH3CH2COCH2CH3CH3OCH2CH3CH3OCHCH2CH3CH3ethoxyethanemethoxyethane2-methoxybutanemethoxycyclohexaneCH3OCH3CH2OCH3CHOCH3CH2COCH3CH3CH3methylethyl1-methylethyl1,1-dimethylpropylmethoxy

26、ethoxy 1-methylethoxy 1,1-dimethylpropoxy diethyl ether( ethyl ether)ethylmethyl ethersec-butylmethyl ethercyclohexylmethyl ether第42頁(yè)/共81頁(yè)OROCOa carbonyl groupan acyl groupa benzoyl group第43頁(yè)/共81頁(yè)OHH3COHCOHHformaldehydeacetaldehydebenzaldehydemethanalethanalphenylmethanalNomenclature of aldehydes an

27、d ketones第44頁(yè)/共81頁(yè)OHOHOHCH3OHCH2CH3CH3benzenecarbaldehydecyclohexanecarbaldehyde4-methylbenzenecarbaldehyde5-ethyl-4-methylcyclohexanecarbaldehydephenylmethanal第45頁(yè)/共81頁(yè)Nomenclature of ketones第46頁(yè)/共81頁(yè)OCH2CH3H3COCH3COCH3H3COCH3acetoneacetophenonebutyrophenonepropanonephenylethanonephenylbutanone2-bu

28、tanonebutyryl benzene or dimethyl ketonemethyl phenyl ketonephenyl propyl ketoneethyl methyl ketone 第47頁(yè)/共81頁(yè)OXRX= OH, a carboxylic acidX= halogen, an acyl halide X= OR, an ester X= OCOR, an acid anhydride X= NRR, an amide 第48頁(yè)/共81頁(yè)OOH第49頁(yè)/共81頁(yè)第50頁(yè)/共81頁(yè)HCOOHCH3COOHH3CH2CCOOHHC=CH2COOHformic acidacet

29、ic acidpropionic acidacrylic acidmethanoic acidethanoic acidpropanoic acidpropenoic acidCOOHCOOHCOOHCH3CH3COOHCOOHCOOHbenzoic acidbenzenecarboxylic acidcyclohexanecarboxylic acid2,4-dimethylcyclopentane-carboxylic acid1,2,4-benzenetricarboxylic acid第51頁(yè)/共81頁(yè)第52頁(yè)/共81頁(yè)methanoyl bromideethanoyl chlorid

30、epropanoyl bromidepropenoyl chlorideformyl bromideacetyl chlorideHCOBrCH3COClH3CH2CCOBrHC=CH2COClmethanoic acidethanoic acidpropanoic acidpropenoic acidCOClCOBrCOBrCH3CH3benzenecarboxylic acidcyclohexanecarboxylic acid2,4-dimethylcyclopantane-carboxylic acidbenzoyl chloridebenzenecarbonyl chloridecy

31、clohexanecarbonyl bromide2,4-dimethylcyclopentane-carbonyl bromide第53頁(yè)/共81頁(yè)R-C-O-C-ROO第54頁(yè)/共81頁(yè)CH3C-O-CHCH3C-O-CCH3OOCH3CHCH2C-O-CCH2CH3OOOOCH3ethanoic anhydrideethanoic methoic anhydride3-methylbutanoic propanoic anhydrideacetic anhydrideacetic formic anhydride第55頁(yè)/共81頁(yè)R-C-O-ROcarbonyl oxygencarbox

32、yl oxygenNomenclature of esters第56頁(yè)/共81頁(yè)CH3C-O-CH2CH3OCH3CHCH2C-O-CH2CH3OBrCH3C-OOethyl ethanoatephenyl ethanoateethyl 3-bromobutanoateethyl acetateCH3C-O- K+OC-O-CH2CH3OC-O-CH2CH3Oethyl benzoatepotassium acetateethyl cyclohexanecarboxylateethyl phenylmethanotepotassium ethanoate第57頁(yè)/共81頁(yè)R-C-NH2OR-C

33、-NHR1OR-C-NR1R2ONomenclature of amides第58頁(yè)/共81頁(yè)CH3C-NH2OCH3CHCH2C-NH2OBrC-NH2OC-NH2O ethanamide 3-bromobutanamidecyclohexanecarboxamidephenylmethanamide acetamidebenzamideCH3C-NHOCH3CHCH2C NOBrCH3CH2CH3N-cyclohexyl ethanamideN-ethyl-N-methyl 3-bromobutanamide第59頁(yè)/共81頁(yè)CNRCNH3CCNCNCHCH2ethanenitrileph

34、enylmethanenitrilepropenenitrileacetonitrilebenzonitrileacrylonitrilemethyl cyanidephenyl cyanide第60頁(yè)/共81頁(yè)nAluminum (鋁)nTin (錫)nLead (鉛)第61頁(yè)/共81頁(yè)第62頁(yè)/共81頁(yè) 另外必須提供微生物的生長(zhǎng)介質(zhì)必須含有諸如硫酸銨、氨水或尿素等含氮化合物，以及無(wú)機(jī)磷酸鹽。此外，必需有的恒定的最佳的pH值和溫度。以青霉素G為例，發(fā)酵過(guò)程在200小時(shí)后完成，細(xì)胞團(tuán)塊經(jīng)過(guò)濾而分離。從濾液中經(jīng)吸收或提取工藝而分離出所需要的活性制劑。細(xì)胞團(tuán)塊，如果并非目的產(chǎn)品，由于其高蛋白質(zhì)含量

35、，可進(jìn)一步用作動(dòng)物飼料 。 Additionally the microorganisms must be supplied in the growth medium with nitrogen-containing compounds such as ammonium sulfate, ammonia, or urea, as well as with inorganic phosphates. Furthermore, constant optimal pH and temperature are required. In the case of penicillin G, the fer

36、mentation is finished after 200 hours, and the cell mass is separated by filtration. The desired active agents are isolated from the filtrate by absorption or extraction processes. The cell mass, if not the desired product, can be further used as an animal feedstuff owing to its high protein content

37、.第63頁(yè)/共81頁(yè) 利用現(xiàn)代重組技術(shù)，已獲得的微生物可以生產(chǎn)原始基因中并未編碼的多肽。修飾過(guò)的大腸桿菌使得產(chǎn)生人類(lèi)胰島素或前胰島素原類(lèi)似物的A-和B-鏈成為可能。經(jīng)分離后再選擇性形成二硫鍵，其最終提純由色析（譜）工序來(lái)決定。通過(guò)這種方式，完全可以不受限制地從任意的動(dòng)物胰腺原料獲得人類(lèi)胰島素。 By modern recombinant techniques microorganisms have been obtained which also allow production of peptides which were not encoded in the original genes.

38、 Modified E. coli bacteria make it thus possible to produce A- and B- chains of human insulin or proinsulin analogs. The disulfide bridges are formed selectively after isolation，and the final purification is effected by chromatographic procedures. In this way human insulin is obtained totally indepe

39、ndently from any pancreatic material taken from animals.第64頁(yè)/共81頁(yè) 其他重要的肽，激素和酶，如人類(lèi)生長(zhǎng)激素（HGH），神經(jīng)活性肽，生長(zhǎng)抑素，干擾素，組織型纖溶酶原激活劑（TPA），淋巴因子，如鈣調(diào)蛋白的鈣調(diào)節(jié)劑，蛋白疫苗，以及作為診斷用單克隆抗體，也是應(yīng)用這種方法合成的。 Other important peptides, hormones, and enzymes, such as human growth hormone (HGH), neuroactive peptides, somatostatin, interferon

40、s, tissue plasminogen activator (TPA), lymphokines, calcium regulators like calmodulin, protein vaccines, as well as monoclonal antibodies used as diagnostics, are synthesized in this way.第65頁(yè)/共81頁(yè) 一個(gè)單一的微生物中所存在的酶或酶系統(tǒng)，可應(yīng)用于控制的立體定向的和位置定向的化學(xué)反應(yīng)。這個(gè)原理在類(lèi)固醇化學(xué)尤其有用。在這里，我們只能提及黃體酮經(jīng)微生物法的11-位羥基化反應(yīng)制得11-羥基黃體酮，一個(gè)用于合成

41、可的松（腎上腺皮質(zhì)酮）的關(guān)鍵產(chǎn)品。今天，分離出的酶很重要，不僅因?yàn)榈矸鄣拿阜ㄌ腔夹g(shù)的重要性以及葡萄糖異構(gòu)化成果糖，而且它們?cè)谟糜谠\斷疾病的無(wú)數(shù)檢測(cè)程序和用于監(jiān)測(cè)治療的酶法分析中也很重要。 The enzymes or enzymatic systems which are present in a single microorganism can be used for directed stereospecific and regiospecific chemical reactions. This principle is especially useful in steroid che

42、mistry. Here we may refer only to the microbiological 11-hydroxylation of progesterone to 11-hydroxyprogesterone, a key product used in the synthesis of cortisone. Isolated enzymes are important today not only because of the technical importance of the enzymatic saccharification of starch, and the i

43、somerization of glucose to fructose, They are also significant in the countless test procedures used in diagnosing illness, and in enzymatic analysis which is used in the monitoring of therapy. 第66頁(yè)/共81頁(yè) 大量的酶本身可以作為活性成分。因此，含有蛋白酶（如糜蛋白酶，胃蛋白酶和胰蛋白酶），淀粉酶和脂肪酶的制劑產(chǎn)品，大多與合成的抗酸藥相配合，以促進(jìn)消化。鏈激酶和尿激酶是重要的溶血栓劑，而天冬酰胺酶則

44、用作治療白血病中的細(xì)胞生長(zhǎng)抑劑。 A number of enzymes are themselves used as active ingredients. Thus preparations containing proteases (e. g. chymotrypsin, pepsin, and trypsin), amylases and lipases, mostly in combination with synthetic antacids, promote digestion. Streptokinase and urokinase are important in throm

45、bolytics, and asparaginase is used as a cytostatic agent in the treatment of leukemia.第67頁(yè)/共81頁(yè) 最后必須提到的是，酶作為生物催化劑在化學(xué)反應(yīng)的重要應(yīng)用，其中立體專(zhuān)一性和選擇性可以得到應(yīng)用。著名例子有酶裂解N-乙?；?D,L-氨基酸的外消旋體而生成L-氨基酸，從芐基青霉素經(jīng)青霉素酰胺酶作用生產(chǎn)8-氨基青霉烷酸，以及天門(mén)冬氨酸酶催化氨對(duì)富馬酸立體專(zhuān)一性加成反應(yīng)以生產(chǎn)L-天門(mén)冬氨酸。 在這些應(yīng)用中，酶可以固載的形式某種方式連接在載體上使用，也可以雜相催化劑的形式來(lái)使用。這是有利的，因?yàn)樗鼈兛梢院苋菀讖姆磻?yīng)

46、介質(zhì)中分離，并回收再利用。 Finally mention must be made of the important use of enzymes as biocatalysts in chemical reactions where their stereospecificity and selectivity can be used. Known examples are the enzymatic cleavage of racemates of N-acetyl-D,L-amino acids to give L-amino acids, the production of 8-am

47、inopenicillanic acid from benzylpenicillin by means of penicillinamidase and the aspartase-catalysed stereospecific addition of ammonia to fumaric acid in order to produce L-aspartic acid. In these applications the enzymes can be used in immobilized forms-somehow bound to carriers - and so used as h

48、eterogeneous catalysts. This is advantageous because they can then easily be separated from the reaction medium and recycled for further use.第68頁(yè)/共81頁(yè)OOHOHONSHHH2NOCH3CH3COOHNSHHONHOCOOHCH3CH3benzylpenicillinAminopenicillanic acidpenicillinamidaseFumaric acidNH2OOHOHOaspartaseL-aspartic acid第69頁(yè)/共81

49、頁(yè) 另一個(gè)基于蛋白酶專(zhuān)一性作用的重要工藝是應(yīng)用于半合成人胰島素的生產(chǎn)。這從豬胰島素開(kāi)始，其中在B鏈的30-位的丙氨酸由于胰蛋白酶選擇性作用被替換為蘇氨酸叔丁基酯。分離(生成的)胰島素酯，水解為人胰島素，最后經(jīng)色析（譜）法程序而純化。 酶的來(lái)源不僅包括微生物，也包括植物的和動(dòng)物的材料。 Another important process depending on the specific action of proteases is applied for the production of semisynthetic human insulin. This starts with pig in

50、sulin in which the alanine in the 30-position of the B-chain is replaced by a threonine tert-butyl ester by the selective action of trypsin. The insulin ester is separated, hydrolyzed to human insulin and finally purified by chromatographic procedures. Sources for enzymes include not only microorgan

51、isms but also vegetable and animal materials.第70頁(yè)/共81頁(yè) 在表1，已經(jīng)顯示，有超過(guò)75藥劑是經(jīng)全合成而獲得。因此，合成路線的知識(shí)是有用的。這樣的理解也使我們能夠認(rèn)識(shí)到中間體和副產(chǎn)品對(duì)制劑的污染。為了將有效的質(zhì)量控制作為登記的要件，許多國(guó)家的登記機(jī)關(guān)要求有對(duì)生產(chǎn)工藝過(guò)程進(jìn)完整的證明文件。藥物合成的知識(shí)也給研發(fā)化學(xué)家提供了有益的激勵(lì)。 In Table 1 it was already shown that over 75% of all pharmaceutical agents are obtained by total synthesis.

52、 Therefore knowledge of the synthetic routes is useful. Understanding also makes it possible to recognize contamination of the agents by intermediates and by- products. For the reason of effective quality control the registration authorities in many countries demand as essentials for registration a

53、thorough documentation on the production process. Knowledge of drug syntheses provides the R&D chemist with valuable stimulation as well.第71頁(yè)/共81頁(yè) 對(duì)于所有的藥學(xué)活性化合物而言，既不存在優(yōu)選的結(jié)構(gòu)類(lèi)型，也不存在優(yōu)選的反應(yīng)類(lèi)型。這就意味著（藥物合成知識(shí)）幾乎覆蓋了有機(jī)化學(xué)的全部領(lǐng)域和金屬有機(jī)化學(xué)的部分領(lǐng)域。不過(guò)，因大量的起始原料和中間體更較為常用；所以，了解它們?cè)醋猿跫?jí)化學(xué)品的制備可能性是非常有用的?；谶@個(gè)原因，在本書(shū)的某些地方，也適當(dāng)?shù)仃U明了特別重

54、要中間體的樹(shù)狀圖。這些后面的中間體是產(chǎn)生龐大制劑的合成工藝中的關(guān)鍵化合物。 There are neither preferred structural classes for all pharmaceutically active compounds nor preferred reaction types. This implies that practically the whole field of organic and in part also organometallic chemistry is covered. Nevertheless, a larger number of

55、 starting materials and intermediates are more frequently used，and so it is useful to know the possibilities for their preparation from primary chemicals. For this reason it is appropriate somewhere in this book to illustrate a tree of especially important intermediates. These latter intermediates a

56、re the key compounds used in synthetic processes leading to an enormous number of agents. 第72頁(yè)/共81頁(yè) 大多數(shù)情況下，所涉及得化學(xué)品是需大量生產(chǎn)的。以類(lèi)似的方式，這些以工業(yè)芳香族化合物甲苯、苯酚和氯苯為基礎(chǔ)的中間體的情況也確實(shí)如此。此外，在表格可能會(huì)列出關(guān)鍵的化合物，這在合成中追蹤（彼此的）交叉關(guān)系會(huì)有用。 For the most part chemicals are involved which are produced in large amounts. In a similar way th

57、is is also true for the intermediates based on the industrial aromatic compounds toluene, phenol and chloro-benzene. Further key compounds may be shown in a table which can be useful in tracing cross-relationships in syntheses.第73頁(yè)/共81頁(yè) 除了實(shí)際的起始原料和中間體，還需要溶劑既作為反應(yīng)介質(zhì)，也用于通過(guò)重結(jié)晶而純化（的過(guò)程）。常用的溶劑是甲醇、乙醇、異丙醇、丁醇、

58、丙酮、醋酸乙酯、苯、甲苯和二甲苯。在較小程度上，在特殊的反應(yīng)中使用的有乙醚、四氫呋喃、乙二醇醚、N,N-二甲基甲酰胺（DMF）和二甲基亞砜（DMSO）。 In addition to the actual starting materials and intermediates solvents are required both as a reaction medium and for purification via recrystallization. Frequently used solvents are methanol, ethanol, isopropanol, butanol

59、, acetone, ethyl acetate, benzene, toluene and xylene. To a lesser extent diethyl ether, tetrahydrofuran, glycol ethers, dimethylformamide (DMF) and dimethyl sulphoxide (DMSO) are used in special reactions.第74頁(yè)/共81頁(yè) 大量使用的試劑，不僅有酸類(lèi)（鹽酸，硫酸，硝酸，醋酸），還有無(wú)機(jī)的和有機(jī)的堿（氫氧化鈉、氫氧化鉀、碳酸鉀、碳酸氫鈉、氨水、三乙胺、吡啶）。此外，輔助的化學(xué)品包括活性炭和催

60、化劑。所有這些補(bǔ)充的化學(xué)品（如同中間體一樣）都可以成為最終產(chǎn)品中雜質(zhì)的來(lái)源。 Reagents used in larger amounts are not only acids (hydrochloric acid, sulfuric acid, nitric acid, acetic acid) but also inorganic and organic bases (sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, triethylamine, pyridin

61、e). Further auxiliary chemicals include active charcoal and catalysts. All of these supplementary chemicals (like the intermediates) can be a source of impurities in the final product.第75頁(yè)/共81頁(yè) 1969年，世界衛(wèi)生組織（WHO）發(fā)布了保障藥品質(zhì)量的專(zhuān)著中。附錄二是有關(guān)“藥品賠償和質(zhì)量保障的適當(dāng)?shù)囊?guī)范（參見(jiàn)WHO技術(shù)報(bào)告NO. 418，1969年，附錄二；技術(shù)報(bào)告NO. 567，1975年，附錄1A）。在

62、此期間，這本專(zhuān)著已成為廣為人知的“藥品生產(chǎn)質(zhì)量管理規(guī)范”或“GMP規(guī)則”，現(xiàn)在在藥品生產(chǎn)過(guò)程中應(yīng)當(dāng)遵守這些規(guī)則。它們構(gòu)成了有關(guān)藥品生產(chǎn)的品質(zhì)證書(shū)的相互認(rèn)同和檢驗(yàn)生產(chǎn)設(shè)施的基礎(chǔ)。 In 1969 the WHO published a treatise on Safeguarding Quality in Drugs. Appendix 2 is concerned with the Proper Practice for Reparation and Safeguarding Quality in Drugs (WHO Technical Report No. 418,1969, Append

63、ix 2; No. 567,1975, Appendix 1A). This has in the meantime become known as Good Manufacturing Practices or GMP rules，and these should now be obeyed in drug production. They form the basis for mutual recognition of quality certificates relating to the production of pharmaceuticals and for inspections

64、 of the production. facilities.第76頁(yè)/共81頁(yè) 長(zhǎng)期以來(lái)，美國(guó)藥品管理局美國(guó)聯(lián)邦食品及藥物管理局（FDA）已發(fā)布類(lèi)似于世界衛(wèi)生組織（WHO）規(guī)則的有關(guān)藥品制劑的法令法規(guī)，而且要求嚴(yán)格執(zhí)行這些法規(guī)。同對(duì)成品的要求一樣，但凡出口到美國(guó)的藥物，需要由FDA對(duì)其生產(chǎn)設(shè)施進(jìn)行合格的檢查。 For a long time the US drug authority, the Food and Drug Administration (FDA), has issued regulations for the preparation of drugs analogous to

65、 the WHO rules, and it applies these strictly. Exports of drugs to the USA, like those of finished products, require regular inspection of the production facilities by the FDA. 第77頁(yè)/共81頁(yè) 在此僅僅指出的是，這種嚴(yán)格控制不僅適用于產(chǎn)品，也適用于原材料（起始原料的監(jiān)控），還適用于中間體。顯然，對(duì)生產(chǎn)的工藝設(shè)備和衛(wèi)生設(shè)備，以及存儲(chǔ)區(qū)域也必須符合規(guī)定的條件。 It may merely be noted here th

66、at such careful control applies not only to the products, but also to the raw materials (control of starting materials), and also to the intermediates. Clearly, the technical and hygienic equipment of the production and the storage areas have to fulfill set conditions.第78頁(yè)/共81頁(yè) 由于只有少數(shù)的化合物，諸如乙酰水楊酸（阿司匹林）、撲熱息痛（對(duì)乙酰氨基苯酚）和維生素，是要大量生產(chǎn)的；大多數(shù)的實(shí)際生產(chǎn)是在多功能（多產(chǎn)品）的設(shè)備中進(jìn)行的。必須特別注意通過(guò)良好的清潔使用過(guò)的設(shè)備，來(lái)避免其他產(chǎn)品的交叉污染。對(duì)所有儲(chǔ)存的中間體和產(chǎn)品進(jìn)行仔細(xì)的描述和定義是必要的。 Since only a few compounds, such as acetylsalicylic acid, paracetamol and vitamins,