富马酸泰诺福韦酯与工业设计
戴强UOP先进甲醇制烯烃技术助力烯烃行业发展Reduced
19
煤到聚合物– 操作成本
煤通过MTO制取聚合物 : 富有竞争力的操作成本和富有吸引力的投资回报率
20
MTO 总结
• 乙烯和丙烯需求保持强劲增长。
• MTO技术提供了一条从煤或天然气为原料甲醇制乙烯、丙烯的新路径。
– 富有竞争力的先进的工艺技术
– 轻烯烃产品收率高(> 89%) ；生产每吨轻烯烃仅消耗2.6吨甲醇
– 现金成本= $523/MT 聚合物
– 净成本= $1000/MT 聚合物投资回收期短, 内部投资回报收益高, 高净现值
– 投资回报年限 = 2.6 年 – 投资回报率 = 20.0% – 净现值 (20 年) = $34 亿
Advanced MTO enables excellent Coal to Polymers economics
– 低催化剂磨损，每处理一吨甲醇进料催化剂损耗仅为0.17公斤
– 高压力设计，投资低
– 宽泛的丙乙比(1.25 到1.8)
– 单系列装置轻烯烃产能可达180万吨/年
– 副产品C4烯烃可以生产后续的B1-B2和丁二烯
• 2013 首次在南京惠生清洁能源公司, 到2106年底有3套装置投入运行
• 与全球煤和天然气的利用息息相关
收率提升受益于OCP 集成设计
100 90 80
Other high value products Ethylene Propylene
70
60
50
40
30
20
10
0 Naphtha
MTP
MTO
Advanced MTO
12
2.6 甲醇消耗每吨生产轻烃
100
90
80
15 Design for Quality
using a process called tailor welding -- manufacturers now laser weld two sheet metal blanks of different thickness and then stamp the blank.
9
Tailor-Welded Blank Example
5
B. Design Reviews
n
Nearly all companies today have formal design review processes (periodic reviews of product & process designs). These reviews involve multiple disciplines (cross-functional) n design engineers, process engineers, manufacturing, marketing n goals: product~process integration and product~customer integration While most companies use cross-functional design reviews, authority levels may vary by degree of functional integration (next slide).
15 design for quality designquality productstqm pathammett designingquality ntoproducts "design designcost lever product (design) engineering 10:1* process engineering 4:1* factory conditions 1:1* effectiveforce quality costs (non-world class) cost worldclass manufacturers design costsassociated poorquality influencedmore product/process design than factory operations. design quality productstqm pathammett measuringdesign quality whichfunctional requirements design(fitness use,feature- based quality). designpermits rational manufacturing (design specificationrequirements achievable(realistic tolerances). designlasts reasonablelife (low failure rate) lowmaintenance costs (reliability). sometechniques used designquality ntoproducts robustdesign designreview teams/ concurrent engineering assembly(dfma) nspection(install poke-yoke devices) qualityfunction deployment (qfd) failuremode effectsanalysis (fmea) al echniques pr ovi de st ruct ure designi ng qual product designquality productstqm pathammett robustdesign
富马酸泰诺福韦酯片说明书(英文)
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VIREAD safely and effectively. See full prescribing informationfor VIREAD.VIREAD® (tenofovir disoproxil fumarate) tabletsInitial U.S. Approval: 2001WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OFHEPATITISSee full prescribing information for complete boxed warning. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use ofnucleoside analogs, including VIREAD. (5.1)• Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic functionshould be monitored closely in these patients. Ifappropriate, resumption of anti-hepatitis B therapy may bewarranted. (5.2)---------------------------RECENT MAJOR CHANGES--------------------------- Indications and Usage (1.2) 10/2010 Dosage and Administration (2.1, 2.2, 2.3) 10/2010 Warnings and PrecautionsNew Onset or Worsening Renal Impairment (5.3) 10/2009Decreases in Bone Mineral Density (5.6) 03/2010----------------------------INDICATIONS AND USAGE--------------------------- VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)VIREAD is indicated for the treatment of chronic hepatitis B in adults. (1)---------------------------DOSAGE AND ADMINISTRATION-------------------- • Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults: 300 mg once daily taken orally withoutregard to food. (2.1)• Recommended dose for the treatment of HIV-1 in pediatric patients (≥12 years of age and ≥35 kg): 300 mg once daily taken orally without regard to food. (2.2)• Dose recommended in renal impairment in adults:Creatinine clearance 30-49 mL/min: 300 mg every 48 hours.(2.3)Creatinine clearance 10-29 mL/min: 300 mg every 72 to 96 hours.(2.3)Hemodialysis: 300 mg every 7 days or after approximately 12hours of dialysis. (2.3)-----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 300 mg. (3)--------------------------------CONTRAINDICATIONS------------------------------ None. (4)--------------------------WARNINGS AND PRECAUTIONS--------------------- • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in patients at risk. Avoid administeringVIREAD with concurrent or recent use of nephrotoxic drugs. (5.3) • Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA and TRUVADA). Do not administer in combination with HEPSERA. (5.4) • HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviralcombination regimen in HIV-infected patients with or without HBV coinfection. (5.5)• Decreases in bone mineral density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6)• Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.7)• Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.8)• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and considertreatment modification. (5.9)-----------------------------ADVERSE REACTIONS--------------------------------In HIV-infected subjects: Most common adverse reactions (incidence ≥10%, Grades 2 - 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. (6)In HBV-infected subjects with compensated liver disease: most common adverse reaction (all grades) was nausea (9%). (6)In HBV-infected subjects with decompensated liver disease: most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or /medwatch------------------------------DRUG INTERACTIONS--------------------------------• Didanosine:Coadministration increases didanosineconcentrations. Use with caution and monitor for evidence ofdidanosine toxicity (e.g., pancreatitis, neuropathy). Considerdose reductions or discontinuations of didanosine if warranted.(7.1)• Atazanavir:Coadministration decreases atazanavirconcentrations and increases tenofovir concentrations. Useatazanavir with VIREAD only with additional ritonavir; monitor for evidence of tenofovir toxicity. (7.2)• Lopinavir/ritonavir:Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.3)----------------------------USE IN SPECIFIC POPULATIONS-------------------• Pregnancy: There is a registry available. Enroll patients by calling 1-800-258-4263.• Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3)• Safety and efficacy not established in patients less than 12 years of age. (8.4)See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient LabelingRevised: October 2010 FULL PRESCRIBING INFORMATION: CONTENTS*WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS1 INDICATIONS AND USAGE1.1 HIV-1 Infection1.2 Chronic Hepatitis B2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in Adults2.2 Recommended Dose in Pediatric Patients (≥12 Years ofAge and ≥35 kg)2.3 Dose Adjustment for Renal Impairment in Adults3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis5.2 Exacerbation of Hepatitis after Discontinuation ofTreatment5.3 New Onset or Worsening Renal Impairment5.4 Coadministration with Other Products5.5 Patients Coinfected with HIV-1 and HBV5.6 Decreases in Bone Mineral Density5.7 Fat Redistribution5.8 Immune Reconstitution Syndrome5.9 Early Virologic Failure6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Didanosine7.2 Atazanavir7.3 Lopinavir/Ritonavir7.4 Drugs Affecting Renal Function8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Patients with Impaired Renal Function10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Clinical Efficacy in Patients with HIV-1 Infection14.2 Clinical Efficacy in Patients with Chronic Hepatitis B16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION AND FDAAPPROVED PATIENT LABELING* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITHSTEATOSIS and POST TREATMENT EXACERBATION OF HEPATITISLactic acidosis and severe hepatomegaly with steatosis, including fatalcases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical andlaboratory follow-up for at least several months in patients who discontinueanti-hepatitis B therapy, including VIREAD. If appropriate, resumption ofanti-hepatitis B therapy may be warranted [See Warnings and Precautions(5.2)].1 INDICATIONS AND USAGEInfection1.1 HIV-1VIREAD® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:• VIREAD should not be used in combination with TRUVADA® or ATRIPLA® [See Warnings and Precautions (5.4)].1.2 Chronic Hepatitis BVIREAD is indicated for the treatment of chronic hepatitis B in adults.The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:• This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].• VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease. [See Adverse Reactions (6.1), Clinical Studies(14.2)]• The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions ofefficacy [See Microbiology (12.4), Clinical Studies (14.2)].2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in AdultsFor the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.2.2 Recommended Dose in Pediatric Patients (≥12 Years of Age and ≥35 kg) For the treatment of HIV-1 in pediatric patients 12 years of age and older with body weight ≥35 kg (≥77 lb): The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.2.3 Dose Adjustment for Renal Impairment in AdultsSignificantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].Table 1 Dosage Adjustment for Patients with Altered Creatinine ClearanceCreatinine Clearance(mL/min)aHemodialysis Patients≥50 30–49 10–29Recommended 300 mg Dosing Interval Every 24hoursEvery 48hoursEvery 72 to96 hoursEvery 7 days or after a total ofapproximately 12 hours ofdialysis ba. Calculated using ideal (lean) body weight.b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.VIREAD should be administered following completion of dialysis.The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.3 DOSAGE FORMS AND STRENGTHSVIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.5.3 New Onset or Worsening Renal ImpairmentTenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA®.Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min [See Dosage and Administration (2.3)]. No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.5.4 Coadministration with Other ProductsVIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.4)].Coinfected with HIV-1 and HBV5.5 PatientsDue to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.5.6 Decreases in Bone Mineral DensityAssessment of bone mineral density (BMD) should be considered for adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144. Twenty-eightpercent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range.In a clinical study of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].The bone effects of VIREAD have not been studied in patients with chronic HBV infection.Redistribution5.7 FatIn HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.5.9 Early Virologic FailureClinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.6 ADVERSEREACTIONSThe following adverse reactions are discussed in other sections of the labeling:• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].• Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)]. • Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].• Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].6.1 Adverse Reactions from Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clinical Trials in Adult Patients with HIV-1 InfectionMore than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access studies.The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.Treatment-Naïve PatientsStudy 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.Table 2Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 903 (0–144 Weeks)VIREAD + 3TC + EFVd4T + 3TC + EFV N=299 N=301 Body as a WholeHeadache Pain Fever Abdominal pain Back painAsthenia 14%13% 8% 7% 9% 6% 17% 12% 7% 12% 8% 7% Digestive SystemDiarrhea Nausea Dyspepsia Vomiting 11% 8% 4% 5% 13% 9% 5% 9% Metabolic Disorders Lipodystrophy b1% 8%Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous SystemDepression InsomniaDizziness Peripheral neuropathy cAnxiety 11%5% 3% 1% 6% 10% 8% 6% 5%6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event d18% 12%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.c. Peripheral neuropathy includes peripheral neuritis and neuropathy.d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.Laboratory Abnormalities: With the exception of fasting cholesterol and fastingtriglyceride elevations that were more common in the stavudine group (40% and 9%)compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observedin this study occurred with similar frequency in the VIREAD and stavudine treatmentarms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-TreatedSubjects in Study 903 (0–144 Weeks)VIREAD + 3TC + EFV d4T + 3TC + EFVN=299 N=301Any ≥ Grade 3 Laboratory Abnormality 36% 42%Fasting Cholesterol (>240 mg/dL) 19% 40%Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12%Serum Amylase (>175 U/L) 9% 8%AST (M: >180 U/L; F: >170 U/L) 5% 7%ALT (M: >215 U/L; F: >170 U/L) 4% 5%Hematuria (>100 RBC/HPF) 7% 7%Neutrophils (<750/mm3) 3%1% Fasting Triglycerides (>750 mg/dL) 1% 9%Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaïve subjects received either VIREAD + EMTRIVA® administered in combination withefavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz(N=254). Adverse reactions observed in this study were generally consistent with thoseseen in previous studies in treatment-experienced or treatment-naïve subjects(Table 4).Table 4Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 934 (0–144 Weeks) VIREAD b + FTC + EFV AZT/3TC + EFVN=257 N=254 Gastrointestinal Disorder Diarrhea Nausea Vomiting9% 9% 2% 5% 7% 5% General Disorders and Administration Site Condition Fatigue9% 8% Infections and Infestations SinusitisUpper respiratory tract infectionsNasopharyngitis 8% 8%5% 4% 5%3% Nervous System Disorders Headache Dizziness 6% 8% 5% 7%Psychiatric Disorders Depression Insomnia9% 5% 7% 7% Skin and Subcutaneous TissueDisorders Rash eventc7%9%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, andrash vesicular. Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in AnyTreatment Group in Study 934 (0–144 Weeks)VIREAD a + FTC + EFV AZT/3TC + EFVN=257 N=254Any ≥ Grade 3 Laboratory Abnormality 30% 26%Fasting Cholesterol (>240 mg/dL) 22% 24%Creatine Kinase (M: >990 U/L; F: >845 U/L) 9% 7%Serum Amylase (>175 U/L) 8% 4%Alkaline Phosphatase (>550 U/L) 1% 0%AST (M: >180 U/L; F: >170 U/L) 3% 3%ALT (M: >215 U/L; F: >170 U/L) 2% 3%Hemoglobin (<8.0 mg/dL) 0% 4%Hyperglycemia (>250 mg/dL) 2% 1%Hematuria (>75 RBC/HPF) 3% 2%Glycosuria (≥3+) <1% 1%Neutrophils (<750/mm3) 3%5% Fasting Triglycerides (>750 mg/dL) 4% 2%a. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz.Treatment-Experienced PatientsTreatment-Emergent Adverse Reactions: The adverse reactions seen in treatmentexperienced subjects were generally consistent with those seen in treatment naïvesubjects including mild to moderate gastrointestinal events, such as nausea, diarrhea,vomiting, and flatulence. Less than 1% of subjects discontinued participation in theclinical studies due to gastrointestinal adverse reactions (Study 907).A summary of moderate to severe, treatment-emergent adverse reactions that occurredduring the first 48 weeks of Study 907 is provided in Table 6.。
泰诺福韦的合成工艺研究
泰诺福韦的合成工艺研究王志刚;聂静;王治国【摘要】泰诺福韦是制备抗病毒药物泰诺福韦酯富马酸盐的关键中间体，以腺嘌呤和（ R）－1，2－亚丙基碳酸酯为原料，经开环缩合、取代和水解3步反应制得泰诺福韦。
反应过程用高效液相色谱仪（ HPLC ）进行监测，探讨了反应的最佳工艺：①开环缩合的最佳反应温度为145℃，最佳反应时间为5．5 h；②以叔丁醇镁为碱，取代反应的最佳反应时间为10 h；③采用廉价的三甲基氯硅烷和溴化钠进行水解，最佳反应时间为24 h。
在最优化的条件下总收率达到49．6％。
%Tenofovir is the key intermediate for the antiviral drug tenofovir disoproxil fumarate .Tenofovir is synthesized by adenine and propyl carbonate through ring -opening condensation , substitution reaction and hydrolysis reaction .The process of reaction is monitored by using High Performance Liquid Chromatography ( HPLC) .The optimal reaction conditions are discussed:①The best synthesis condition of ring -opening condensation is at 145 ℃ for 5.5 h.②The best reaction time of substitution reaction is 10 h with magnesium tert-butoxide as alkali .③The best reaction time of hydrolysis reaction is 24 h using cheap trimethylchlorosi-lane and sodium bromide.The overall yield of 49.6 % is obtained under optimal conditions.【期刊名称】《湖北理工学院学报》【年(卷),期】2015(000)005【总页数】4页(P46-49)【关键词】泰诺福韦;合成;工艺【作者】王志刚;聂静;王治国【作者单位】湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003【正文语种】中文【中图分类】O626Key words：tenofovir;synthesis;process泰诺福韦(Tenofovir)，化学名是R-9-(2-磷酸甲氧基丙基)腺嘌呤，CAS号：147127-20-6，是抗病毒药物泰诺福韦酯的关键中间体。
诺氏制药产品DA创意设计提案--songny888资料文档
作品 － 凯洛欣标志设计
7 拥有庞大的管理资料库
产品标志设计方案一
简单的线条勾勒出大脑的形状，同时对中文“凯”字进行变形，让二者有机 的结合在一起。生命如同一棵正茁壮生长的大树，而凯洛欣正是保护、滋养这棵 大树的根系。 本标志构图简洁，融合国际化的设计理念，生命绿与科技蓝更好的昭示出用 科技创造新生的概念。
本画面极具视觉冲击，
张力十足，从而使受众群 体产生强烈的震撼，最终 由此及彼达到对药品药性 的记忆与传播。
创意说明：
腾空而起的新式战斗机代
表了强势及征服，这预示 着凯洛欣一飞冲天的发展 势头，同时飞向不同方向 的三个飞机，有力的阐释 凯洛欣的三重作用功效， 背景中的人物享受的表情 仿佛在幻想，如此强劲的 三重作用机制，真棒.
诺氏制药 产品DA创意设计提案
1 拥有庞大的管理资料库
产品一：凯洛欣产品标志及DA封面创意设计
产品介绍：
诺氏制药集团近年来致力于神经保护剂的开发,如对曲克芦丁脑蛋白水解物注 射液(普洛迪) 和脑苷肌肽注射液(凯洛欣)都进行了一些初步的临床和基础研究。 这些研究遵循了规范的原则并克服了药物单一靶点作用的困惑,初步显示出一 定的疗效。
普洛迪中含有曲克芦丁和脑蛋白水解物，分别作用于神经细胞和血管，体现了双 靶位作用。其中，曲克芦丁能抑制血小板的聚集，有防止血栓形成的作用。同时能对 抗5－羟色胺、缓激肽引起的血管损伤，增加毛细血管抵抗力，降低毛细血管通透性， 可防止血管通透性升高引起的水肿。本品所含的大量活性多肽、多种氨基酸等能透过 血脑屏障，以多种形式作用于中枢神经，调整和改善神经元的代谢，并影响其呼吸链， 具有激活、改善脑内神经递质和酶的活性，保护神经细胞免受各种缺血和神经毒素的 损害。能增加脑组织对葡萄糖的利用，改善脑细胞缺氧状态，对缺氧的脑组织有保护 作用。体现出普洛迪的双重疗效。因此是认知功能障碍及脑卒中恢复期治疗的首选用 药。
年产16000吨L-天门冬氨酸建设项目环境影响报告表
础上编制完成了该项目环境影响报告书。 在报告书编写过程中得到了烟台市环保局、龙口市环保局、相关专家以及建 设单位的大力支持和协助，在此一并表示衷心的感谢。 由于水平所限，书中不足之处难免，敬请专家、领导批评指正。 项目组 2017 年 3 月
年产 16000 吨 L-天门冬氨酸建设项目
总论
第 1 章 总论
1-1
年产 16000 吨 L-天门冬氨酸建设项目
总论
号)； （5） 《国务院关于印发节能减排综合性工作方案的通知》 （国发[2007]15 号） ； （6） 《关于进一步加强危险废物和医疗废物监管工作的意见》 （环发 [2011]19 号） ； （7） 《关于实施〈环境空气质量标准〉 (GB3095-2012) 的通知》 ( 环发 [2012]11 号)； （8） 《环境保护部关于进一步加强环境影响评价管理防范环境风险的通 知》(环发[2012]77 号)； （9） 《关于切实加强风险防范严格环境影响评价管理的通知》 ( 环发 [2012]98 号)； （10） 《危险废物转移联单管理办法》 （国家环境保护总局令 第 5 号） ； （11） 《关于执行大气污染物特别排放限值的公告》 （环境保护部公告 2013 年 第 14 号） ； （12） 《关于印发<建设项目环境影响评价政府信息公开指南>（试行）的 通知》 （环办[2013]103 号） ； （13） 《关于切实加强环境影响评价监督管理工作的通知》(环办[2013]104 号)； （14） 《 关 于 发 布 < 一 般 工 业 固 体 废 物 贮 存 、 处 置 场 污 染 控 制 标 准 > （GB18599- 2001）等 3 项国家污染物控制标准修改单的公告》 （环境保护部公告 2013 年 第 36 号） ； （15） 《关于加强企业环境信用体系建设的指导意见》 （环发[2015]161 号） ； （16） 《关于印发<建设项目环境影响评价信息公开机制方案>的通知 《 （环 发[2015]162 号） ； （17） 《关于发布 < 环境保护部审批环境影响评价文件的建设项目目录 （2015 年本）>的公告》 （环保部公告 2015 年第 17 号） ； （18） 《工业和信息化部关于促进化工园区规范发展的指导意见》 （工信部 原[2015]433 号） ； （19） 《环境保护公众参与办法》 （环境保护部令 2015 年第 35 号） ；
VersaFlow Coriolis 6000选型指南说明书
TABLE V
Hazardous Area Approvals
Hygienic/Sanitary Approvals
None ATEX Ex ia (T1-T6) IEC Ex ia (T1-T6) cFMus Class 1 Div 1 (USA standards) cFMus (Canadian Standards) / Dual seal for liquids’ cFMus (Canadian Standards) / Dual seal for gases’ None NACE according to MRO175 / ISO 15156 and MRO103
SmartLine® VersaFlow Coriolis 6000
CM74 Size 25 Stainless Steel or Hastelloy C
Model Selection Guide
36-CM-16-42
Issue 7
• Broad Range of Operating Temperatures
(Alu or SS mandatory for Cryogenic or High Temperature)
3 point mass flow calibration
5 point mass flow calibration
3 point volume flow calibration
5 point volume flow calibration
TWC 9400 Compact Mount (Not for High Temperature) TWC 9400 Field Mount Other
Requires a separate MSG# to be entered. Either
泰诺福韦中间体PMPA市场调研
泰诺福韦，简称PMPA一、产品信息中文名(R)-9-(2-磷酸甲氧基丙基)-腺嘌呤，泰诺福韦酯中间体PMPA，替诺福韦分子式英文名1-(6-aminopurin-9-yl)propan-2-yloxymethylphosphonic acid，TenofovirCAS No. 147127-20-6分子式C9H14N5O4P分子量287.21二、合成方法三、生产厂家厂家设计产能生产状态备注上海迪赛诺化学制药200吨/年泰诺福韦在生产上海迪赛诺同大丰海天医药合作在盐城建设有限公司生产，目前属于上海迪赛诺的控股公司，15年9月更名盐城迪赛诺制药有限公司安徽贝克联合制药有在生产主要出口替诺福韦原料药600吨/年富马酸替诺限公司福韦二吡呋酯中间体荆门市帅邦化学科技有限公司300吨/年在生产16年月出口印度PMPA14.7吨乐平市赛复乐医药化工有限公司100吨/年在生产16年通过贸易公司出口至少PMPA9.8吨，富马酸泰诺福韦酯至少2.275吨埃斯特维华义制药有限公司2012年环评显示90吨/年，实际产能约200吨/年在生产16年出口143.75吨富马酸泰诺福韦酯，属于出口量最大的一家，埃斯特维华义制药有限公司是西班牙ESTEVEQUIMICA公司与杭州华东医药集团子公司（义乌市华义投资有限公司）的第二家合资公司，主要从事非专利化学原料药的研发、生产与销售。
四、国内外下游产品客户1、下游产品及用途1.1泰诺福韦简介泰诺福韦（Tenofovir），化学名R-9-（2-磷酸甲氧基丙基）腺嘌呤（简称PMPA），是抗病毒药物富马酸泰诺福韦酯的关键中间体。
富马酸泰诺福韦酯是一种新型的开环核苷酸类逆转录酶抑制剂，是一种酯类前药，口服吸收后迅速转变成泰诺福韦。
美国FDA在2001年和2008年分别批准其用于艾滋病（HIV）和慢性乙型肝炎（HBV）的治疗。
富马酸泰诺福韦酯，中文名：替诺福韦，通用名称：富马酸替诺福韦二吡呋酯片；商品名称：韦瑞德，英文名称：Tenofovir Disoproxil Fumarate Tablets，替诺福韦是世界卫生组织WHO艾滋病治疗指南推荐的艾滋病抗病毒一线药物。
富马酸泰诺福韦酯合成工艺改进
富马酸泰诺福韦酯合成工艺改进发布时间：2021-03-03T01:27:33.603Z 来源：《中国科技人才》2021年第3期作者：静桂兰胡文俊[导读] 近年来随着艾滋病感染者数量的不断上升，昂贵的治疗费用使患者们无门可依，这已经成为严重的社会问题，所以，抗HIV的治疗已经不仅仅局限于医学范畴了，而实验研究证明泰诺福韦酯具有良好的抗HIV活性，其用于对其他药物的HIV效果已得到验证，另外其抗HBV的活性也相当高，所以富马酸泰诺福韦酯极具市场潜力。
静桂兰胡文俊浙江嘉福新材料科技有限公司浙江省嘉兴市 314102摘要：近年来随着艾滋病感染者数量的不断上升，昂贵的治疗费用使患者们无门可依，这已经成为严重的社会问题，所以，抗HIV的治疗已经不仅仅局限于医学范畴了，而实验研究证明泰诺福韦酯具有良好的抗HIV活性，其用于对其他药物的HIV效果已得到验证，另外其抗HBV的活性也相当高，所以富马酸泰诺福韦酯极具市场潜力。
但传统的合成工艺比较复杂，杂质残留较大，质量不高，我们要探寻新的简单易操作的富马酸泰诺福韦酯合成工艺。
关键词：富马酸泰诺福韦酯；合成工艺；简单易操作富马酸泰诺福韦酯化学名：9- [（R）-2-[[双[[（异丙氧擬基）氧基]甲氧基]磷酸基]甲氧基]丙基]腺嘌呤富马酸盐，是美国Gilead公司研制的核苷酸逆转录酶抑制剂。
于2001年批准其上市用于治疗艾滋病，2008年又批准其用于治疗慢性乙型肝炎。
富马酸泰诺福韦酯本身具有天然的良好性能，值得开发。
一、富马酸泰诺福韦酯物化性质1.1富马酸泰诺福韦酯图1-1为富马酸泰诺福韦酯分子结构图分子式：C19H30N5O10P分子量：635.51性状：白色结晶粉末熔点：113-115℃沸点：642.7℃at760mmHg闪点：342.5℃水溶性：在二甲基甲酰胺中易溶，在甲醇中溶解；在水、乙腈中微溶。
1.2富马酸泰诺福韦酯用途富马酸泰诺福韦酯是一种抗病毒药物，针对这款药物的特性来看，作用特点与替诺韦福类似，具有非常好的抗病毒性药物，但本药的细胞毒性更强，化学及酶学的稳定性也更强不过本药品的活性代谢的产物PMPA在细胞内迅速蓄积，因而在细胞内的重摄取也迅速增快，进而发挥强效抗逆转录病毒作用。
年产800吨富马酸单乙酯的车间工艺设计
毕业论文课程设计说明书题目：年产800吨富马酸单乙酯的车间工艺设计姓名：学号：班级：指导老师：成绩：应用化学专业课程设计任务书1．设计原始数据年产量；800吨年工作日：280天生产工艺原理：以马来酸酐、乙醇为原料，氯化铝为催化剂，生产制备富马酸单乙酯。
反应温度：醇解60℃，异构化回流温度。
反应时间：醇解2小时，异构化2小时，反应完毕后,用甲苯结晶、冷却、过滤、烘干称量,计算收率。
其中富马酸单乙酯产率为80%。
其它工艺参数通过查资料自己确定。
2．物料规格原料与产物规格（纯度）马来酸酐98.0%乙醇99.5%氯化铝98.0%甲苯98%3．工艺计算物料衡算热量衡算设备计算4．编制设计说明书设计说明书的内容：一、总论（1）概述所设计产品的性能、用途和在国民经济中或对人民生活的重要性；该产品的市场需求，该产品的生产方法及特点。
（2）文献通过查阅国内外期刊文献，简述该产品的生产试验概况，国内外的生产现状和发展趋势。
（1000字以上）（3）项目来源由教师指定的课题（4）设计产品所需的主要材料的规格、来源以及水、电、汽的供应情况、结合设计地区供应情况加以说明。
二、生产流程和生产方案的确定根据查阅文献或实际调查所掌握的情况，或依据科学试验报告或小试结果进行放大设计，分析各种生产方法及其特点。
简要叙述自己设计所选定的生产方法的依据和特点。
画出一个简单流程图。
三、工艺计算包括物料衡算与能量衡算，计算结果汇总于物料衡算表和热量衡算表中，并将计算基准转换为生产能力的基准，包括时间基准和单位产品基准。
四、主要设备的工艺计算和设备选型根据设计任务工作量的大小，对反应釜进行工艺计算并进行选型。
并根据生产能力，按物料衡算和热量衡算的结果，对其它设备都作为辅助设备进行选型。
如泵、压缩机、换热器、槽罐等。
五、原材料、动力消耗定额六、车间成本估算七、环境保护及安全措施八、设计的体会和收获九、参考文献十、附工程图纸（1）带控制点的工艺流程图（2）主要设备装配图参考书《化工设计手册》（上、下册），国家医药管理局上海医药设计院编《精细化工反应器及车间工艺设计》（左识之主编），华东理工大学出版社《化工制图》《工程制图》（化工）《化工工艺设计概论》学生签名：目录第一章概述 (1)1.1 产品介绍 (1)1.2 原料介绍 (1)第二章生产方法的选择和流程设计 (4)2.1 工艺流程说明及操作步骤 (4)2.2 富马酸单乙酯生产流程框图[5-7] (4)第三章物料衡算及能量衡算 (5)3.1 物料衡算 (6)3.2 能量衡算[8] (7)3.2.1 热量平衡式 (7)3.2.2 热量衡算 (7)第四章设备计算和选型 (10)4.1 反应釜的结构和材质 (10)4.2 反应釜中物质的平均密度ρm的计算 (10)4.3 反应釜的计算和选型[9-10] (10)第五章投资估算和成本估算 (13)5.1 原料消耗量[11-12] (13)5.2 车间水、电、水蒸气的消耗量M (13)第六章环境保护措施 (16)6.1 环境保护 (16)6.2 安全措施 (16)第七章结论 (19)第八章主要设备装配图 (20)8.1 反应釜结构图（见附页） (20)8.2 富马酸单乙酯生产工艺流程图（见附页） (20)第九章心得体会 (21)第十章参考文献 (23)第一章概述1.1 产品介绍富马酸酯是一类重要的有机合成中间体和新型的化学防霉剂，具有低毒、高效、使用不受 pH 值局限、无残留等优点[1]。
富马酸磷丙替诺福韦的相关专利分析
富马酸磷丙替诺福韦的相关专利分析作者：王晓晨陆皞然来源：《河南科技》2018年第18期摘要：富马酸磷丙替诺福韦是一种新型核苷类逆转录酶抑制剂（NRTI），临床用于治疗慢性乙型肝炎。
本文通过对富马酸磷丙替诺福韦的相关专利进行分析，为我国医药企业对于该药物的研究提供建议。
关键词：富马酸磷丙替诺福韦；专利；分析中图分类号：R969.1 文献标识码：A 文章编号：1003-5168（2018）18-0052-03Analysis of the Patent about Tenofovir Alafenamide FumarateWANG Xiaochen LU HaoranAbstract：Tenofovir Alafenamide Fumarate is new NRTI. It is used to treat hepadnaviridae. This paper analyzed the patent about Tenofovir Alafenamide Fumarate， in order to make recommendations for pharmaceutical companies.Key words：Tenofovir Alafenamide Fumarate；patent；analysis1 概述富马酸磷丙替诺福韦（Tenofovir Alafenamide Fumarate，TAF），是美国吉利德科学公司（Gilead Science）研制的新型核苷类逆转录酶抑制剂（NRTI），于2016年11月10日获得美国食品药品监督管理局（FDA）批准上市，商品名Vemlidy，用于慢性乙型肝炎患者的治疗，于2016年12月19日获得日本医药品医疗器械综合机构批准上市，又于2017年1月9日获得欧洲药物管理局批准[1]。
TAF是吉利德已上市药物Viread（替诺福韦酯，TDF）的升级改良版。
半富马酸替诺福韦艾拉酚胺的合成工艺优化
半富马酸替诺福韦艾拉酚胺的合成工艺优化ZHOU Yueying;ZENG Haoyue;QIU Jingxiao;HUANG Chengyong;WU Zhen;WANG Liqiang【摘要】对最新抗乙肝药物半富马酸替诺福韦艾拉酚胺(TAF)的合成工艺进行优化研究.以腺嘌呤(1)为原料,与(R)-碳酸丙烯酯反应得到(R)-9-(2-羟丙基)腺嘌呤.然后,将产物经磷叶立德取代,水解反应得到(R)-9-((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤.最后,将所得产物经取代、酰化、缩合、成盐反应得到目标产物TAF,并对各步反应条件进行优化.结果表明:总收率达32.1％(以腺嘌呤计),较原工艺提高23.1％,目标化合物及主要中间体经电子轰击质谱(EI-MS)、核磁共振氢谱(1 H-NMR)、核磁共振碳谱(13 C-NMR)确证结构;与现有文献报道的TAF合成工艺相比,优化后的工艺总收率大幅提高,反应成本降低,反应时间缩短,可避免生产过程中的安全隐患,适合工业化生产.【期刊名称】《华侨大学学报（自然科学版）》【年(卷),期】2019(040)004【总页数】8页(P527-534)【关键词】半富马酸替诺福韦艾拉酚胺;腺嘌呤;(R)-碳酸丙烯酯;工艺改进【作者】ZHOU Yueying;ZENG Haoyue;QIU Jingxiao;HUANG Chengyong;WU Zhen;WANG Liqiang【作者单位】;;;;;【正文语种】中文【中图分类】R914.5慢性乙型肝炎(chronic hepatitis B，CHB)是由乙型肝炎病毒(HBV)持续感染引起的慢性肝脏炎症性疾病.全球约有三分之一人口曾感染HBV，其中2.4亿人为慢性HBV感染者.据世界卫生组织(WHO)报道，全球30%的肝硬化患者和50%肝癌患者都由HBV感染所致，2013年，全球约有68万人死于HBV感染，HBV感染已经成为全球公认的重大健康问题[1-3].半富马酸替诺福韦艾拉酚胺(tenofovir alafenamide humifumarate，TAF)是一种治疗乙肝的新型核苷逆转录酶抑制剂，尚未在中国上市及进口[4].TAF是富马酸替诺福韦酯(TDF)的新一代替诺福韦(PMAP)口服前药，TAF的Ⅲ期临床试验数据显示，25 mg的TAF与300 mg现有的抗乙肝一线药物TDF的抗乙肝病毒效果相当,且TAF对肾和骨骼的毒性更小，安全性更好[5-6]，是目前疗效最好的核苷类乙肝药物.文献中报道的TAF合成路线主要有4条[7-15].TAF的合成路线需经过中间体(R)-9-(2-羟丙基)腺嘌呤或(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤,并以此为二次原料，经过数步反应制得TAF.但现有的合成方法存在目标产物收率低，反应后处理程序繁多，合成成本高，工业生产效率低，存在安全性问题等缺点，不适合工业化放大生产.因此,本文选择对吉利德公司的原研路线[9]进行优化，以腺嘌呤为起始原料，与(R)-碳酸丙烯酯反应得到(R)-9-(2-羟丙基)腺嘌呤；然后，经磷叶立德取代、水解反应得到(R)-9-(((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤，再经取代、酰化、缩合、成盐反应制备得到TAF.1 实验材料1.1 仪器与试剂DF-101S型集热式恒温加热磁力搅拌器，X-5型显微熔点测定仪(河南省巩义市予华仪器有限责任公司);1200型高效液相色谱仪(DAD检测器，美国安捷伦公司);Q Exactive型高分辨质谱仪(美国Thermo Scientific公司);核磁共振波谱仪(瑞士Bruker公司).腺嘌呤、(R)-碳酸丙烯酯、对甲苯磺酰氧基甲基膦酸二乙酯(优级纯，上海邦成化工有限公司)；其余试剂为市售分析纯.1.2 实验方法1.2.1 TAF的合成方法文中研究的TAF合成路线，如图1所示.图1 TAF合成路线Fig.1 Synthetic route of TAF1.2.2 (R)-9-(2-羟丙基)腺嘌呤(化合物2)的制备将腺嘌呤(4.1 g,0.030 mol)，(R)-碳酸丙烯酯(3.98 g，0.039 mol)和氢氧化钠(0.08 g，0.002 mol)置于12 mL二甲基甲酰胺(DMF)中，130 ℃加热搅拌过夜.待薄层色谱(TLC)监控反应完全.将反应冷却至100 ℃，加入甲苯(25.2 mL)并于室温搅拌2 h，抽滤，滤饼用丙酮(5mL×2)冲洗，于80 ℃真空干燥得到类白色粉末，即化合物2(5.37 g)，其收率为91.6%(文献[9]为75%)，熔点为188.6～189.7 ℃，样品质量分数为96.8%(高效能液相色谱(HPLC)面积归一化法，检测条件:色谱柱为 Sinochrom ODS-BPC18(4.6 mm×150 mm,5 μm);流动相为V(甲醇)∶V(水)=25∶75,V为体积;流速为1.0 mL·min-1;检测波长为260 nm;进样量为10 μL;柱温为30 ℃).1H-NMR(400 MHz,Deuterium Oxide)，化学位移(δ):7.88(s，2H)，4.16～4.00(m，2H)，3.94(d，J=8.6 Hz，1H)，1.15(s，3H).化合物2的核磁共振氢谱,如图2所示.1.2.3 (R)-9-[2-(二乙酰氧基膦酰基甲氧基)丙基]腺嘌呤(化合物3)的制备将称取化合物2(5.02 g，0.026 mol)置于DMF(25 mL)中，加热至65 ℃后，在1 h内加入叔丁醇镁(3.58 g，0.021 mol)；当反应升温至78 ℃时，在2 h内加入对甲苯磺酰氧基甲基膦酸二乙酯(16.43 g，0.051 mol)，于75 ℃下反应4 h.冷却反应至50 ℃后，加入冰醋酸调节反应液的pH值至6，蒸出溶剂，加入二氯甲烷(50 mL)和质量分数为20%的NaCl水溶液(30 mL)，搅拌30 min，滤除不溶物；分层取有机层，水层用二氯甲烷(20 mL×2)萃取.加入无水硫酸钠干燥，过滤后将溶剂旋蒸干，得到黄色油状物，即化合物3(7.42 g)，其收率为83.2%，样品质量分数为98.5%(HPLC面积归一化法，检测条件:色谱柱为Sinochrom ODS-BP C18(4.6 mm×150 mm,5 μm);流动相为V(甲醇)∶V(水)=20∶80;流速为1.0 mL·min-1;检测波长为254 nm;进样量为10 μL;柱温为30 ℃).1.2.4 (R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤(化合物4)的制备将化合物3(5.83 g，0.017 mol)和三甲基溴硅烷(7.81 g，0.051 mol)加入乙腈(30 mL)中，于77 ℃下反应3 h，减压蒸馏；将残余物溶解在蒸馏水(30 mL)中，用乙酸乙酯(25 mL)进行萃取，分层取水层；用NaOH调节水层pH值至1.1，放入晶种，再用NaOH调节pH值至2.1，室温搅拌过夜，冷却至4 ℃后过滤的灰色固体，用少量水洗涤，于50 ℃真空干燥得到粗产物.将粗产物放入水(50 mL)中，加热回流4 h；冷却至室温后，将混合物于4 ℃冷却3 h，过滤固体，用少量水和丙酮洗涤，于50 ℃真空干燥，得到白色粉末，即化合物4(3.42 g).其收率为70.2%(文献[9]的收率为50.4%，以化合物2计).1H-NMR(400 MHz,Deuterium Oxide)，化学位移(δ): 8.43～8.23(m，2H)，4.44(dd，J=14.8，3.2 Hz，1H)，4.25(dd，J=14.7，7.0 Hz，1H)，4.00～3.88 (m，1H)，3.65(dd，J=13.2，9.3 Hz，1H)，3.55～3.37(m，1H)，1.13(d，J=6.4 Hz，3H).化合物4的核磁共振氢谱，如图3所示.图2 化合物2的核磁共振氢谱图3 化合物4的核磁共振氢谱 Fig.2 1H-NMR spectrum of compound 2 Fig.3 1H-NMR spectrum of compound 4 1.2.5 (R)-9-(((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤(化合物5)的制备将称取化合物4(2.87 g,0.010 mol)，亚磷酸三苯酯(6.52 g,0.021 mol)，4-二甲氨基吡啶(DMAP)(0.122 g,0.001 mol)，三乙胺(0.20 g,0.002 mol)于40 mL无水吡啶中，氮气保护条件下,将反应升温至75 ℃，反应72 h；TLC监控至反应完成后，减压蒸馏将反应液的溶剂蒸干，得到橙黄色油状物.加入水(15 mL)和乙酸乙酯(25 mL)，分层取水层，水层再用乙酸乙酯(15 mL)萃取一次，取水层.用浓盐酸将水层的pH值调至3，搅拌2 h至晶体析出，过滤，滤饼用少量乙醇洗涤，得到白色固体粗产物，于70 ℃真空干燥，得到白色粉末，即化合物5(2.56 g).其收率为70.6%(文献[9]的收率为50.7%)，样品的质量分数为99.2%(HPLC面积归一化法，检测条件:色谱柱为Sinochrom ODS-BP C18(4.6 mm×150 mm,5 μm);流动相为V(甲醇)∶V(水)=35∶65;流速为1.0 mL·min-1;检测波长为254 nm;进样量为10 μL;柱温为30 ℃).1H-NMR(400 MHz，Deuterium Oxide)，化学位移(δ): 8.27(s，1H)，8.18(s，1H)，7.18(t，J=7.7 Hz，2H)，7.04(t，J=7.4 Hz，1H)，6.68(d，J=7.9 Hz，2H)，4.38(dd，J=15.0，2.9 Hz，1H)，4.22(dd，J=14.7，8.7 Hz，1H)，4.04(d，J=8.1 Hz，1H)，3.79(dd，J=13.7，7.9 Hz，1H)，3.53(dd，J=13.7，9.0 Hz，1H)，1.24(d，J=6.1 Hz，3H).化合物5的核磁共振氢谱,如图4所示.1.2.6 (R)-9-(((2-磷酰氯基单苯酯基)甲氧基)丙基)-腺嘌呤(化合物6)的制备将化合物5(2.50 g,0.007 mol)、亚硫酰氯(SOCl2，1.90 g,0.016 mol)溶于乙腈(40 mL)中，在75 ℃下搅拌至反应物完全溶解，蒸除溶剂，得到褐色油状物，即化合物6(2.45 g)，其收率为93.4%.1.2.7 替诺福韦艾拉酚胺(化合物7)的制备在氮气保护下，将上一步反应所得的化合物6(2.40 g，0.006 mol)冷却至室温后加入二氯甲烷(35 mL)并冷却至-29 ℃，在-18 ℃条件下，于1 h内加入含有(L)-丙氨酸异丙酯(1.84 g，0.014 mol)的二氯甲烷溶液(30 mL)；然后，在-18～-11 ℃的条件下缓慢加入三乙胺(1.92 g，0.019 mol)，室温反应，TLC监控反应完全.将反应完毕的反应液用质量分数为10%的磷酸二氢钠水溶液(5 mL×5)洗涤，无水硫酸钠除去有机反应液中的水分，过滤.用二氯甲烷(30 mL)冲洗，减压蒸馏得粗产物.将粗产物加入至质量分数为20%的氯化钠溶液(10 mL)洗涤，洗涤数次后，TLC监控直到原料点除去，分离得浅褐色油状产物，即化合物7(2.17 g)，其收率72.3%(文献[9]的收率为46.8%，以化合物5计).1H-NMR(400 MHz，DMSO-d6),化学位移(δ):8.13(d，J=13.8 Hz，2H)，8.11(s，1H)，7.34～7.11(m，5H)，7.05(d，J=7.9 Hz，2H)，5.65(m，J=11.2 Hz，1H)，4.85(m，J=6.2 Hz，1H)，4.28(dd，J=14.5，3.7 Hz，1H)，4.15(dd，J=14.4，6.5 Hz，1H)，3.96～3.70(m，4H)，1.18～1.05(m，12H).化合物7的核磁共振氢谱,如图5所示.图4 化合物5的核磁共振氢谱图5 化合物7的核磁共振氢谱Fig.4 1H-NMR spectrum of compound 5 Fig.5 1H-NMR spectrum of compound71.2.8 半富马酸替诺福韦艾拉酚胺(化合物8)的制备将化合物7(2.00 g，0.004 mol)，富马酸(0.14 g，0.002 mol)加入至乙腈(50 mL)中，加热回流直至化合物溶解，趁热过滤，将滤液缓慢冷却至0～5 ℃并静置过夜，过滤，滤饼用冷乙腈(5 mL×2)洗涤，真空干燥得到白色粉末状产物，即化合物8(1.99 g)，其收率为88.9%，样品的质量分数为99.9%，光学异构体质量分数为0.14 %(HPLC面积归一化法，检测条件:色谱柱为Sinochrom ODS-BP C18(4.6 mm×150 mm,5 μm)；流动相为V(乙腈)∶V(醋酸铵)(10 mmol·L-1,pH=6.2)=30∶70；流速为1.0 mL·min-1；检测波长为260 nm；进样量为10 μL；柱温为30 ℃.HPLC光学异构体检测条件:色谱柱为CHIRALPAK AD-H(250 mm×4.6 mm,5 μm)；V(正己烷)∶V(异丙醇)=80∶20(流动相加质量分数为0.1%的乙二胺调节pH值)；检测波长为260 nm；流速为1.0 mL·min-1；柱温为30 ℃；进样体积为10 μL).ESI-MS(m/z):477.3；[M+H]+.1H-NMR (400 MHz，DMSO-d6),化学位移(δ): 8.13(d，2H)，7.31～7.12 (m，5H)，7.05(dt，J=7.3，1.2 Hz，2H)，6.64(s，1H)，5.65(dd，J=12.0，10.4 Hz，1H)，4.85(hept，J=6.3 Hz，1H)，4.28(dd，J=14.4，3.7 Hz，1H)，4.16(s，1H)，3.94～3.75(m，4H)，1.14(dd，J=8.4，6.6 Hz，9H)，1.07(d，J=6.2 Hz，3H).13C NMR (101 MHz，DMSO-d6)，化学位移(δ):173.36，173.32，166.45，156.40，152.86，150.70，150.62，150.23，141.87， 134.45， 129.94， 124.81， 121.01，118.83，75.88，68.36， 65.34， 63.80，49.52， 47.30， 21.85， 20.78，17.09.IR(KBr)σ(cm-1): 3 360.4， 3 176.7， 2 982.9， 2 890.3， 1 748.2， 1 663.8， 1 606.9，1 420.8，1 301.2，1 206.3， 1 152.3， 1 104.1，924.2.化合物8的核磁共振氢谱、核磁共振碳谱、高效液相色谱、质谱和红外光谱图，分别如图6～10所示.图10中：η为透过率.图6 化合物8的核磁共振氢谱图7 化合物8的核磁共振碳谱Fig.6 1H-NMR spectrum of compound 8 Fig.7 13C-NMR spectrum of compound8图8 化合物8的高效液相色谱图图9 化合物8的质谱图Fig.8 High performance liquid chromatogram of compound 8 Fig.9 Mass spectrumof compound 8图10 化合物8的红外光谱图Fig.10 Infrared spectrum of compound 82 合成工艺的优化2.1 (R)-9-(2-羟丙基)腺嘌呤反应的合成机理是腺嘌呤在碱性条件下形成氮负离子,从而进攻(R)-碳酸丙烯酯上正电荷密集的碳原子，促使其脱去一分子二氧化碳;接着，腺嘌呤上的氮负离子和碳原子链接后形成带有氧负离子的(R)-9-(2-羟丙基)腺嘌呤;最后，该氧负离子与一分子腺嘌呤反应生成一分子(R)-9-(2-羟丙基)腺嘌呤和一分子腺嘌呤氮负离子.其中，氢氧化钠在该反应中起催化作用，有利于腺嘌呤脱去氢离子从而进攻(R)-碳酸丙烯酯上的碳原子促使反应发生.通过分析反应机理和前期实验得知,n(腺嘌呤)∶n((R)-碳酸丙烯酯)和n(氢氧化钠)∶n(腺嘌呤)对实验收率有较大影响，n为物质的量.因此,通过单因素考察实验分别考察n(腺嘌呤)∶n((R)-碳酸丙烯酯)和n(氢氧化钠)∶n(腺嘌呤)对(R)-9-(2-羟丙基)腺嘌呤收率的影响，结果如图11,12所示.图11 n(腺嘌呤)∶n((R)-碳酸丙烯酯)对化合物2收率的影响图12 n(氢氧化钠)∶n(腺嘌呤)对化合物2收率的影响Fig.11 Effect of molar ratio ofn(adenine)∶n((R)-propylene) on yield of compound 2 Fig.12 Effect of molar ratio of n(NaOH)∶n(adenine) on yield of compound 2由图11可知:腺嘌呤与(R)-碳酸丙烯酯的物质的量的比对化合物2的收率有较为突出的影响;当n(腺嘌呤)∶n((R)-碳酸丙烯酯)为1.0∶1.0～1.0∶1.3时，收率随着比值的增大而增加;当n(腺嘌呤)∶n((R)-碳酸丙烯酯)为1.0∶1.3时，收率达最大值81.7%，而后趋于平稳.由图12可知:n(氢氧化钠)∶n(腺嘌呤)对中间体7收率影响较大，当n(氢氧化钠)∶n(腺嘌呤)为1∶25～1∶15时，收率随着比值的减小而增加；当n(氢氧化钠)∶n(腺嘌呤)为1∶15时，收率达到最大值91.6%，而后逐渐减小.由实验可知，当n(腺嘌呤)∶n((R)-碳酸丙烯酯)为1.0∶1.3，n(氢氧化钠)∶n(腺嘌呤)为1∶15时，反应收率达最大值91.6%.2.2 (R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤图13 n(化合物3)∶n(三甲基溴硅烷)的物质的量比对化合物4收率的影响Fig.13 Effect of molar ratio of n(compound 3)∶n(TMBS) on yield of compound 4该反应机理为三甲基溴硅烷(TMBS)与(R)-9-[2-(二乙酰氧基膦酰基甲氧基)丙基]腺嘌呤上发生亲电取代反应后，水解生成三甲基硅醇和(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤.由反应机理可知，反应溶剂和脱烷基化试剂三甲基溴硅烷在反应中起重要作用，因此，单因素考察n(化合物3)∶n(三甲基溴硅烷)对化合物4收率的影响，如图13所示.由图13可知：n(化合物3)∶n(三甲基溴硅烷)对反应收率的影响较大；当比值为1∶3时，反应收率达最大值59.4%.推测可能是因为溶剂中含有较多水，使部分三甲基溴硅烷水解失去脱烷基化作用.因此，增加三甲基溴硅烷的用量可提高反应收率，故选择n(化合物3)∶n(三甲基溴硅烷)为1∶3为该步实验的反应条件.通过单因素考察反应溶剂对化合物4收率的影响，结果表明：以乙腈作为反应溶剂时，化合物4的收率为70.2%，远高于以二甲基甲酰胺和二氯甲烷作溶剂时的收率，二者分别为59.4%和61.2%.究其原因，可能是乙腈和二氯甲烷溶剂中含水分较少，可以减少脱烷基化试剂的水解，从而使反应收率提高，而原料在乙腈中的溶解效果比在二氯甲烷中要好，反应在乙腈溶剂中更易形成均相体系.因此，在后续研究中将采用乙腈作为该步反应的溶剂.2.3 (R)-9-(((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤原合成工艺路线采用二环己基碳二亚胺(DCC)作催化剂，(R)-9-[2-(膦酰基甲氧基)丙基]腺嘌呤与苯酚反应制得(R)-9-(((2-磷酸单苯酯基)甲氧基)丙基)-腺嘌呤.其中，苯酚为高毒性试剂，且用DCC做催化剂的催化效率不高，DCC反应后生成的1，3-二环己基脲(DCU)难以除净，需要经过繁琐的后处理步骤.根据预实验结果发现，以另一工业化试剂亚磷酸三苯酯代替高毒性试剂苯酚、高效催化剂DMAP代替DCC进行反应，省去了原合成路线多次过滤，先碱调再酸调pH值的众多繁琐步骤，化合物5的收率由50.7%提高至70.6%.2.4 替诺福韦艾拉酚胺在制备替诺福韦艾拉酚胺的过程中，原工艺采用柱层析的方法对产物进行纯化，在工业化生产中。
年产300吨肉毒素原料药的工厂设计方案
肉毒素原料药，作为一种重要的生物制剂，具有广泛的临床应用前景。
然而，年产300吨肉毒素原料药的工厂设计方案却十分复杂，需要考虑多方面的因素才能确保生产的安全、高效和可持续。
本文将从工厂设计的必要性、技术要点、设备选择、安全管理以及未来发展方向等方面进行深入探讨，希望能够为读者提供全面的知识和深刻的理解。
1. 工厂设计的必要性肉毒素原料药的生产是一个严谨而复杂的过程，需要在生物制药、化学工程、微生物学、生物化学等多个领域的知识相结合，因此工厂设计显得尤为重要。
只有通过合理的设计，才能够确保生产过程的安全可靠，生产效率的提高，以及成本的控制。
而一个年产300吨肉毒素原料药的工厂更需要严谨的设计和规划，以满足大规模生产的需求。
2. 技术要点在进行年产300吨肉毒素原料药的工厂设计时，有几个关键的技术要点需要重点考虑。
首先是生物反应器的设计，包括选择合适的菌株，培养基的配方，培养条件的控制等。
其次是提取工艺的设计，需要考虑提取设备的选择以及提取工艺的优化。
最后是纯化工艺的设计，包括色谱分离、超滤、结晶等步骤的设计与优化。
这些技术要点将直接影响到产品的质量和产量，因此需要充分的研究和实践。
3. 设备选择在工厂设计过程中，设备的选择是至关重要的一环。
针对年产300吨肉毒素原料药的工厂，需要选择容量大、性能稳定的生物反应器、提取设备和纯化设备等。
为了确保生产的稳定和连续，还需要选择合适的自动化设备和控制系统。
只有确保设备的稳定性和可靠性，才能够保证整个生产过程的安全和高效。
4. 安全管理肉毒素原料药的生产涉及到生物安全和化学安全两大领域，因此在工厂设计中需要重视安全管理。
在生物安全方面，需要建立规范的生物安全操作流程，实行严格的微生物菌种管理和实验室条件控制。
而在化学安全方面，则需要确保危险化学品的安全使用与储存，建立完善的应急预案和安全管理体系，以应对突发情况。
5. 未来发展方向随着生物制药技术的不断发展，肉毒素原料药的工厂设计也将朝着智能化、数字化的方向发展。