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104987-11-3

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104987-11-3 Usage

Overview

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. Tacrolimus was first extracted from the fermentation broth of Streptomyces tsukuba, a soil microbe found in Tsukuba, Japan.1 The name tacrolimus is derived by taking the ‘t’ for Tsukuba, the name of the mountain where the soil sample was extracted, ‘acrol’ for macrolide and ‘imus’ for immunosuppressant.[2] Although structurally unrelated to cyclosporin, tacrolimus shows a similar spectrum of immunosuppressive effects to this agent at the cellular and molecular level. Initial studies indicated that tacrolimus was a powerful immunosuppressant, displaying approximately 100-fold greater in vitro potency than cyclosporin in inhibiting T cell activation. Subsequent in vivo studies have shown tacrolimus to be effective both in suppressing spontaneous and experimental autoimmune disease, and in preventing allograft and xenograft rejection in animal models of organ transplantation. Initially, tacrolimus was used for systemic immunosuppression of patients who had undergone allograft transplants to stop them from rejecting their new grafts. Soon, however, through the benefit of the serendipity of science, it was noticed that tacrolimus could produce favorable results in skin disorders in some of the patients who had undergone transplantation. The discovery of tacrolimus has thus lead to greater understanding of skin pathology, for example of atopic dermatitis.[3] Subsequently, other topical applications of tacrolimus were reported and the use of this agent in dermatology is gradually expanding. Figure 1 The chemical structure of Tacrolimus

Indication and administrations

It is used after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.

Pharmacodynamics

Tacrolimus was absorbed topically by intact skin at rates of 3.1, 4.9 and 6.8 ng/cm2 per hour, for the 0.03%, 0.1% and 0.3% ointment concentrations, respectively.[1,2] Interestingly, tacrolimus was absorbed regardless of occlusion at significantly higher rates in damaged skin, with percutaneous penetration of 40 ng/cm2 per hour. Thus, while on topical therapy, the patient’s skin will absorb progressively lower quantities of the agent as the lesions heal. This self-regulatory property of tacrolimus is a major advantage, as it should result in fewer adverse effects over the course of treatment.[4] In one randomized, double-blind study, a 3-week course of twice daily, topically applied tacrolimus ointment 0.03%, 0.1% and 0.3% resulted in blood concentrations below 0.25 ng/mL in most patients.[5] This low systemic absorption rate is typical of the majority of clinical cases. The mean time taken to attain the highest blood concentration of tacrolimus is between 5 and 6 h after application in adults and 2.5 h in children.[6] In another study, the bioavailability of topical tacrolimus was found to be lower than 0.5%. 6 Furthermore, tacrolimus does not seem to accumulate, either in the skin or blood, following repeated applications.[7] When taken orally, the absorption of tacrolimus is erratic and poor. The bioavailability of the drug ranges from 5% to 67%. 8 Intravenous administration of tacrolimus has resulted in the highest relative tissue concentrations in the spleen, lung and kidneys, followed by heart, skin and muscle, then fat and bone marrow and finally by liver, bone and blood.[9] During topical administration, there is no evidence of cutaneous metabolism. Systemically, tacrolimus metabolism is mediated by the cytochrome P450 3A4 isoenzyme. It is metabolized in the liver, by CYPIA and CYPIIIA.[8] In vitro studies have identified eight different metabolites. When SMS 201-995 is administered via the intraperitoneal route, the effects of tacrolimus are enhanced and thus may enable lower doses of the latter to be used.[10] When administered systemically, tacrolimus is eliminated in bile. It is cleared at 2.25 L/h, with a half-life of 40 h. 1 It has been found that paediatric transplant patients under 6 years old have higher weight-normalized clearance of tacrolimus, as compared with older children and adults.

Mode of action

Tacrolimus is a prodrug that enters the T cells and binds to immunophilins, forming a complex that binds competitively and blocks calmodulin.[2] This has the spin-off effect of not activating phosphatase calcineurin, which disables the dephosphorylation of NF-AT and subsequently inhibits entry of NF-AT into the nucleus, suppressing gene transcription. The final result is a decreased responsiveness of T cells to antigens. Tacrolimus can also exert a broad range of immunomodulatory effects on various skin disorders by binding to cell surface steroid receptors and inhibiting mast cell adhesion, inhibiting the release of mediators from mast cells and basophils, decreasing intercellular adhesion molecule-1 and E-selectin lesional blood vessel expression, and downregulating the expression of IL-8 receptor and Fcε RI on Langerhans cells.[11-13] Langerhans cells are considered to be important in the pathophysiology of many inflammatory diseases.[14] There is speculation that the features involved in the activation of Langerhans cells are common with T-cell activation; in other words, there is a dependence on calcineurin in the activation of Fcε RI-specific transcription factor.[15] Tacrolimus may downregulate the expression of FcεRI. Langerhans cells and other CD1a+ skin dendritic cells are important targets of tacrolimus.[14] It has also been suggested that tacrolimus is able to increase levels of p53.2 Topical tacrolimus has been shown to decrease cytokine mRNA levels of IL-1α, IL-1β and macrophage inflammatory protein (MIP)-2, which results in lymph node cell proliferation.16,17 Tacrolimus inhibits the transcription and release of cytokines, for example, IL-2, Il-3, IL-4, IL-5, interferon-γ, tumor necrosis factor-α, and granulocyte-monocyte colony stimulating factor.[18] Additionally, the production of T-helper 1 (Th1) and Th2 cytokines is inhibited by tacrolimus.[18]

Side effects

Different sources of media describe the Side effects of 104987-11-3 differently. You can refer to the following data:
1. Owing to its potent activity as an immunosuppressant, tacrolimus has a number of adverse effects when administered orally or intravenously following transplant operations. Nephrotoxicity, represented by elevated creatinine, blood urea nitrogen, hyperkalaemia and reduction of the glomerular filtration rate, as well as vasoconstrictive effects, such as hypertension are among the most serious adverse effects.[19-22] There are also various neurotoxic adverse effects that can occur with systemic therapy. The major ones include mutism, aphasia, encephalopathy, seizures, psychosis, coma and focal disturbances. These reactions have an incidence of 5–10%. [23,24] Minor adverse effects such as headaches, transient, tremors, paraesthesias, photophobias, somnolence and insomnia occur in approximately 20% of individuals.[25,26] Systemic tacrolimus can also cause adverse reactions in the gastrointestinal system, causing diarrhoea, nausea, constipation, anorexia and vomiting. Respiratory disorders such as dyspnoea, pleural effusion and atelectasis, and cutaneous disorders, such as pruritus or a rash may develop. Other adverse effects include fever, pain, peripheral oedema, arthralgia and asthenia. Hypersensitivity reactions may also occur and may be due castor oil derivatives in the parenteral formulation.[24]
2. Local irritant reactions (burning, stinging, erythema) are a common side effect, but these usually resolve within the first few days of treatment. The major benefit of topical tacrolimus over topical corticosteroids is that tacrolimus does not cause atrophy, striae, or telangiectasia, even with chronic use.

References

Different sources of media describe the References of 104987-11-3 differently. You can refer to the following data:
1. 1 Ruzicka T, Assmann T, Homey B. Tacrolimus: The drug for the turn of the millennium? Arch Dermatol 1999; 135: 574–580. Lawrence ID. Tacrolimus (FK506): experience in dermatology. Dermatol Ther 1998; 5: 74–84. Michel G, Kemeny L, Homey B, Ruzicka T. FK506 in the treatment of inflammatory skin disease: promises and perspectives. Immunol Today 1996; 17: 106–108. Bieber T. Topical tacrolimus (FK506): a new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 1998; 102: 555–557. Ruzicka T, Bieber T, Schopf E et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997; 337: 816–821. Alaiti S, Kang S, Fiedler VC et al. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998; 38: 69–76. Hanifin JM, Chan S. Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies. J Am Acad Dermatol 1999; 41: 72–77. Laurema AI, Granlund H, Reitamo S. Use of the newer immunosuppressive agents in dermatology. Bio Drugs 1997; 8: 96–106. Shirbacheh MV, Jones JW, Harralson TA et al. Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb. J Pharmacol Exp Ther 1999; 289: 1196–1201. Perego C, Lattuada D, Casnici C et al. Evidence that SMS 201–995 enhances the immunosuppressive effect of FK506. Int J Immunopharmacol 1998; 20: 479–490. Fleischer AB. Treatment of atopic dermatitis: Role of tacrolimus ointment as a topical noncorticosteroid therapy. J Allergy Clin Immunol 2000; 104: S126–S130. Wollenberg A, Bieber T. FK-506/Tacrolimus. In: Burg G, Dummer RG, editors. Strategies for Immunointerventions in Dermatology. Springer-Verlag, Heidelberg, 1997: 53–57. Columbo M, Bochner BS, Marone G. Human skin mast cells express functional beta1 integrins that mediate adhesion to extracellular martix proteins. J Immunol 1995; 154: 6058–6064. Panhans-Gro? A, Novak N, Kraft S et al. Human epidermal Langerhans’ cells are targets for the immnosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001; 107: 345–352. Reitamo S. Tacrolimus: a new topical immunomodulatory therapy for atopic dermatitis. J Allergy Clin Immunol 2001; 107: 445–448. Nagai H, Hiyama H, Matsuo A et al. FK-506 and cyclosporin A potentiate the IgE antibody production by contact sensitization with hapten in mice. J Pharmacol Exp Ther 1997; 283: 321–327. Homey B, Assmann T, Vohr H-W et al. Topical FK506 suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during primary skin immune responses. J Immunol 1998; 160: 5331–5340. Leung DYM, Soter NA. Cellular and immunologic mechanisms in atopic dermatitis. J Am Acad Dermatol 2001; 44: S1–S12. Nash RA, Etzioni R, Storb R et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. Blood 1995; 85: 3746–3753. Nielsen FT, Leyssac PP, Kemp E et al. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995; 10: 334–340. Nasr IS. Topical tacrolimus in dermatology. Clin Exp Dermatol 2000; 25: 250–254. Compendium of Pharmaceuticals Specialties, 35th edn. Webcom Limited, Toronto, 2000: 1287–1292. Manez R, Jain A, Marino IR, Thomson AW. Comparative evaluation of tacrolimus (FK506) and cyclosporin A as immunosuppressive agents. Transplant Rev 1995; 9: 63–76. Nousari Hossein C, Sragovich A, Kimyai-Asadi A et al. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999; 40: 265–268. Ohashi Y, Minegishi M, Fujie H et al. Successful treatment of steroid-resistant severe acute GVHD with 24-h continuous infusion of FK506. Bone Marrow Transplant 1997; 19: 625–627. Jegasothy BV, Ackerman CD, Todo S et al. Tacrolimus (FK506) – A new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128: 781–785.
2. 1) Yu et al. (2006), Effects of cyclosporine A, FK506 and rapamycin on calcineurin phosphatase activity in mouse brain; IUBMB Life, 58 429

Description

Different sources of media describe the Description of 104987-11-3 differently. You can refer to the following data:
1. FK-506 is a potent immunosuppressant in the same molecular class as cyclosporin A and rapamycin . Its mechanism of action involves the formation of a high affinity complex (Ki = 0.2 nM) with FK-506 binding protein 12 (FKBP12). This complex then inhibits the activity of the calcium/calmodulin-dependent protein phosphatase, calcineurin, leading to disruption of T cell activation. The physiological effects of FK-506 also include regulation of nitric oxide neurotoxicity, neurotransmitter release, and regulation of Ca2+ release via the ryanodine and inositol-(1,4,5)-trisphosphate (IP3) receptors. In the latter case, FKBP12 forms a tight complex with both ryanodine and IP3 receptors which can be disrupted by FK-506, thereby rendering the receptors leaky to Ca2+.
2. Tacrolimus, isolated from the microorganism Streptomyces tsukubaensis, is a macrolide immunosuppressant developed by Fujisawa for organ transplantation. It displays similar but more potent immunosuppressive activity than cyclosporin. It inhibits both cell mediated and humoral immune responses. In animal models of organ transplantation, tacrolimus has been shown to prolong survival of hepatic, renal, cardiac, small intestine, pancreatic and skin allografts and to reverse cardiac and renal allograft rejection. It has been used effectively in humans as rescue or primary immunosuppressant therapy in liver or kidney transplantation. Compared to cyclosporin, tacrolimus causes reduced incidence of infectious complications and of hypertension and hypercholesterolemia for the allograft recipients. In common with cyclosporin, tacrolimus binds with high affinity to a family of cytoplasmic immunosuppressant binding proteins, the immunophilins. This tight complex is proposed as the biologically active moiety that interacts with intracellular molecules involved in signal transduction.It inhibits phosphatase activity of calcineurin, an action that may impair the generation and/or activation of nuclear transcription factors required for lymphokine (particularly interleukin-2) gene expression. Tacrolimus has also been reported to have potential in multiple sclerosis, psoriasis, rheumatoid arthritis and uveitis associated with Behcet‘s disease.

Chemical Properties

White Crystalline Solid

Originator

Fujisawa (Japan)

Uses

Different sources of media describe the Uses of 104987-11-3 differently. You can refer to the following data:
1. An immunosuppressant that blocks T cell proliferation in vitro by inhibiting the generation of several lymphokines, especially IL-2. Shown to inhibit the activity of FK-506 binding protein, thereby reversing its effects on sarcoplasmic reticulum Ca+2 release.
2. FK-506 (Tacrolimus) is a macrolide immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system
3. Tacrolimus (fujimycin) was discovered as a potent inhibitor of IL2 production in a targeted search for novel immunosuppressants. Tacrolimus acts by blocking T cell proliferation in vitro by inhibiting the generation of several lymphokines, notably the original target IL-2. Tacrolimus inhibits the activity of FK-506 binding protein, Ca2+-dependent phosphatase and calcineurin, and activates NF-κB through phosphorylation and degradation of IκBα.
4. treatment of Cushing's syndrome
5. For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart,

Definition

ChEBI: Tacrolimus is a macrolide containing a 23-membered lactone ring, originally isolated from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Indications

Different sources of media describe the Indications of 104987-11-3 differently. You can refer to the following data:
1. Tacrolimus is a macrolide lactone originally derived from Streptomyces tsukubaensis. Although structurally unrelated to cyclosporine, tacrolimus has a very similar mechanism of action; that is, it blocks the production of proinflammatory cytokines by T lymphocytes by inhibiting calcineurin.Tacrolimus, however, appears to be 10 to 100 times as potent as an immunosuppressive. Oral tacrolimus (FK506) is used for prevention of organ rejection in recipients of renal and hepatic transplants.
2. Tacrolimus (Prograf) is a second-generation immunosuppressive agent that has been approved for use in liver transplantation. Its efficacy for other transplantations is being evaluated. It has properties similar to those of cyclosporine except that weight for weight it is 10 to 100 times more potent. It is a macrolide antibiotic that selectively inhibits transcription of a specific set of lymphokine genes in T lymphocytes (e.g., IL-2, IL-4, and interferon-) and binds to cytoplasmic proteins in lymphocytes. Although the binding proteins (cytophilins) for cyclosporine and tacrolimus are different, they share similar functions in that the cytophilins are important for the intracellular folding of proteins. It is speculated that these proteins are important in regulating gene expression in T lymphocytes and that both drugs somehow interfere in this process. Absorption of tacrolimus from the gastrointestinal (GI) tract is variable. It is extensively metabolized in the liver and excreted in the urine.As with cyclosporine, nephrotoxicity is its principal side effect.

Manufacturing Process

The novel 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatrcyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FR-900506), substance can be produced by culturing a FR-900506 substance(s)-producing strain belonging to the genus Streptomyces (e.g. Streptomyces tsukubaensis No. 9993, FERM BP-927) in a nutrient medium.FermentationA culture medium (160 ml) containing glycerin (1%), corn starch (1%), glucose (0.5%), cottonseed meal (1%), dried yeast (0.5%), corn steep liquor (0.5%) and calcium carbonate (0.2%) (adjusted to pH 6.5) was poured into each of ten 500 ml-Erlenmeyer flasks and sterilized at 120°C for 30 min. A loopful of slant culture of Streptomyces tsukubaensis No. 9993 was inoculated to each of the medium and cultured at 30°C for 4 days on a rotary shaker. The resultant culture was inoculated to a medium containing soluble starch (5%), peanut powder (0.5%), dried yeast (0.5%), gluten meal (0.5%), calcium carbonate (0.1%) and Adekanol (deforming agent, Trade Mark, maker Asasi Denka Co.) (0.1%) (150 liters) in a 200-liter jar-fermentor, which had been sterilized at 120°C for 20 min in advance, and cultured at 30C for 4 days under aeration of 150 liters/minutes and agitation of 250 rpm.Isolation and PurificationThe cultured broth thus obtained was filtered with an aid of diatomaseous earth (5 kg). The mycelial cake was extracted with acetone (50 liters), yielding 50 liters of the extract. The acetone extract from mycelium and the filtrate (135 L) were combined and passed through a column of a non-ionic adsorption resin "Diaion HP-20" (Trade Mark, maker Mitsubishi Chemical Industries Ltd.) (10 L). After washing with water (30 L) and 50 % aqueous acetone (30 L), elution was carried out with 75 aqueous acetone. The eluate (30 liters) was evaporated under reduced pressure to give residual water (2 L). This residue was extracted with ethyl acetate (2 L) three times. The ethyl acetate extract was concentrated under reduced pressure to give an oily residue. The oily residue was mixed with twice weight of acidic silica gel (special silica gel grade 12, maker Fuji Devison Co.), and this mixture was slurried in ethyl acetate. After evaporating the solvent, the resultant dry powder was subjected to column chromatography of the same acidic silica gel (800 ml) which was packed with n-hexane. The column was developed with nhexane (3 L), a mixture of n-hexane and ethyl acetate (4:1 v/v, 3 L) and ethyl acetate (3 L). The fractions containing the object compound were collected and concentrated under reduced pressure to give an oily residue. The oily residue was dissolved in a mixture of n-hexane and ethyl acetate (1:1 v/v, 30 ml) and subjected to column chromatography of silica gel (maker Merck Co., Ltd. 230-400 mesh) (500 ml) packed with the same solvents system. Elution was carried out with a mixture of n-hexane and ethyl acetate (1:1 v/v, 2 liters and 1:2 v/v, 1.5 L) and ethyl acetate (1.5 L). Fractions containing the first object compound were collected and concentrated under reduced pressure to give crude FR-900506 substance (3 g) in the form of yellowish powder.This powder of the FR-900506 substance could be transformed into a form of white crystals by recrystallization thereof from acetonitrile. Melting point: 127°-129°C.

Brand name

Prograf (Astellas); Protopic (Astellas).

Therapeutic Function

Immunosuppressive

General Description

Immunosuppressant that blocks T-cell proliferation in vitro by inhibiting the generation of several lymphokines, especially IL-2. Shown to inhibit the activity of FK-506 Binding Protein, thereby reversing its effects on sarcoplamic reticulum Ca2+ release. Shown to inhibit the Ca2+-dependent phosphatase, Calcineurin (Cat. No. 539565), as well as Na+-K+-ATPase in nephron segments. Also shown to inhibit aldosterone-induced synthesis of Giα-3 protein.

Biochem/physiol Actions

Product does not compete with ATP.

Clinical Use

A topical formulation (Protopic) has recently been approved for treatment of moderate to severe atopic dermatitis in children and adults who have not responded to other therapies. Levels of systemic absorption are low even when applied to a relatively large body surface area.

Veterinary Drugs and Treatments

Different sources of media describe the Veterinary Drugs and Treatments of 104987-11-3 differently. You can refer to the following data:
1. Tacrolimus has recently been studied at the University of Tennessee College of Veterinary Medicine where investigators found it equally effective as cyclosporine and effective for cyclosporine-resistant cases of KCS. It exerts its effects through a mechanism similar to that of cyclosporine, however exact mechanisms of action in causing tear production are still being determined.
2. Tacrolimus ointment may be of benefit in veterinary patients in the adjunctive treatment of atopic dermatitis, discoid lupus erythematosus, pemphigus erythematosus or foliaceous, pinnal vascular disease, alopecia areata, vitiligo and for perianal fistulas (terminal phase or maintenance treatment after cyclosporine therapy). Unlike topical corticosteroids, tacrolimus or pimecrolimus do not have atrophogenic or metabolic effects associated with long-term or large area treatment. Tacrolimus acts similarly as cyclosporine, namely inhibiting T-lymphocyte activation primarily by inhibiting the phosphatase activity of calcineurin. It also inhibits the release of inflammatory cytokines and mediators from mast cells and basophils.

in vitro

tacrolimus (fk506) has been reported to inhibit the interleukin 2(il-2) production and the response of mixed lymphocyte culture. in addition, tacrolimus (fk506) added to the cell cultures has been revealed to inhibit murine or human mixed lymphocyte reactivity and the generation of cytotoxic t cells. furermor, tacrolimus (fk506) has also been reported to dose-dependently suppress the production of various cytokines including il-2, il-3, il-4, and γ-interferon, in response to different stimulis. besides, tacrolimus has shown its efficacy in the prevention of allograft rejection in animal transplant models. tacrolimus has been found to be significantly efficient in experimental hepatic allografts, and has hepatotrophic properties [1].

Drug interactions

Potentially hazardous interactions with other drugs Ciclosporin: may increase the half-life of ciclosporin and exacerbate any toxic effects. The two should not be prescribed concomitantly. Care should be taken when converting from ciclosporin to tacrolimus. Tacrolimus levels increased by: amlodipine, atazanavir, basiliximab, boceprevir, bromocriptine, chloramphenicol, cimetidine, cortisone, danazol, dapsone, diltiazem, ergotamine, ethinyloestradiol, felodipine, fosamprenavir, gestodene, grapefruit juice, imidazole and triazole antifungals, lidocaine, lansoprazole, possibly levofloxacin, macrolides, midazolam, nicardipine, nifedipine, norethisterone, omeprazole, pantoprazole, posaconazole, ranolazine; ritonavir, saquinavir, Chinese herbal remedies containing extracts of Schisandra sphenanthera, tamoxifen, theophylline, verapamil and voriconazole. Tacrolimus levels decreased by: carbamazepine, caspofungin, fosphenytoin, isoniazid, phenobarbital, phenytoin (fosphenytoin and phenytoin levels possibly increased), primidone, rifampicin, possibly rifabutin and St John’s wort. Increased nephrotoxicity with: aminoglycosides, amphotericin, NSAIDs, sulfamethoxazole, trimethoprim and vancomycin. Increased risk of hyperkalaemia with: potassiumsparing-diuretics and potassium salts. Anticoagulants: possibly increases concentration of dabigatran - avoid. Antipsychotics: avoid with droperidol, increased risk of ventricular arrhythmias. Antivirals: increased risk of nephrotoxicity with acyclovir, ganciclovir, valaciclovir and valganciclovir; concentration affected by efavirenz; concentration of both drugs increased with telaprevir; concomitant use with dasabuvir and ombitasvir/paritaprevir/ ritonavir is not recommended unless the benefits outweigh the risks, if used concomitantly, tacrolimus should not be administered on the day dasabuvir and ombitasvir/paritaprevir/ritonavir are initiated. Beginning the day after dasabuvir and ombitasvir/ paritaprevir/ritonavir are initiated; reinitiate tacrolimus at a reduced dose based on tacrolimus levels. The recommended tacrolimus dosing is 0.5 mg every 7 days, monitor levels at initiation and throughout treatment. Clotrimazole: more than doubles the bioavailability of tacrolimus (US-based researchers report that concomitant clotrimazole substantially increases the relative oral bioavailability of tacrolimus in renal transplant recipients. Inpharma. 2005 Dec 10; 1517: 15). Cytotoxics: concentration of afatinib possibly increased - separate dose by 6-12 hours; use crizotinib with caution; concentration increased by imatinib.

Metabolism

Tacrolimus is extensively bound to erythrocytes in the blood, and variations in red cell binding account for much of the variability in pharmacokinetics. It is extensively metabolised in the liver, mainly by cytochrome P450 isoenzyme CYP3A4, and excreted, primarily in bile, almost entirely as metabolites. Considerable metabolism also occurs in the intestinal wall.There are several metabolites identified. Only one of these has been shown in vitro to have immunosuppressive activity similar to that of tacrolimus. The other metabolites have only weak or no immunosuppressive activity. In systemic circulation only one of the inactive metabolites is present at low concentrations. Therefore, metabolites do not contribute to pharmacological activity of tacrolimus.

Check Digit Verification of cas no

The CAS Registry Mumber 104987-11-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,4,9,8 and 7 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 104987-11:
(8*1)+(7*0)+(6*4)+(5*9)+(4*8)+(3*7)+(2*1)+(1*1)=133
133 % 10 = 3
So 104987-11-3 is a valid CAS Registry Number.
InChI:InChI=1/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19-,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1

104987-11-3 Well-known Company Product Price

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  • Cerilliant

  • (T-049)  Tacrolimus solution  1.0 mg/mL in acetonitrile, ampule of 1 mL, certified reference material

  • 104987-11-3

  • T-049-1ML

  • 2,559.96CNY

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104987-11-3SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 14, 2017

Revision Date: Aug 14, 2017

1.Identification

1.1 GHS Product identifier

Product name Tacrolimus

1.2 Other means of identification

Product number -
Other names FK-506

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:104987-11-3 SDS

104987-11-3Synthetic route

C56H97NO12Si2
118977-96-1

C56H97NO12Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With hydrogen fluoride In acetonitrile at 20℃; for 0.05h;100%
With hydrogen fluoride; acetonitrile In dichloromethane at 0℃; for 0.0833333h;81%
With hydrogen fluoride In acetonitrile at 20℃;81%
24,33-Bis-(t.butyl-dimethylsilyl)-FK 506
133941-75-0

24,33-Bis-(t.butyl-dimethylsilyl)-FK 506

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With hydrogen fluoride In acetonitrile at 50℃; for 0.2h;100%
With hydrogen fluoride In acetonitrile at 20℃; for 2.5h;
14-<(tert-butyldimethylsilyl)oxy>-24,32-bis<(triisopropylsilyl)oxy>-FK506
128685-18-7

14-<(tert-butyldimethylsilyl)oxy>-24,32-bis<(triisopropylsilyl)oxy>-FK506

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With hydrogen fluoride In acetonitrile for 18h; Ambient temperature;73%
C66H101NO11Si2
176656-40-9

C66H101NO11Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With hydrogen fluoride; 3,3-dimethyldioxirane 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h; Yield given. Multistep reaction;
C66H101NO12Si2
197250-11-6

C66H101NO12Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With hydrogen fluoride In acetonitrile at 20℃; for 10h; Cyclization; desilylation;10.5 mg
C55H95NO13Si2

C55H95NO13Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 46 percent / epichlorohydrin / 1,2-dichloro-benzene / 0.05 h / 140 °C
2: 100 percent / aq. HF / acetonitrile / 0.2 h / 50 °C
View Scheme
{1-hydroxy-23,25-dimethoxy-12-[2-(3-methoxy-4-triethylsilanyloxy-cyclohexyl)-1-methyl-vinyl]-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-14-triethylsilanyloxy-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-en-17-yl}-acetaldehyde

{1-hydroxy-23,25-dimethoxy-12-[2-(3-methoxy-4-triethylsilanyloxy-cyclohexyl)-1-methyl-vinyl]-13,19,21,27-tetramethyl-2,3,10,16-tetraoxo-14-triethylsilanyloxy-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-en-17-yl}-acetaldehyde

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 43 percent / epichlorohydrin / 1,2-dichloro-benzene / 0.05 h / 140 °C
2: 100 percent / aq. HF / acetonitrile / 0.05 h / 20 °C
View Scheme
C69H107NO12Si2
197250-10-5

C69H107NO12Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 100 percent / dimethyl dioxirane / acetone / 2.17 h / -50 - -26 °C
2: 10.5 mg / aq. HF / acetonitrile / 10 h / 20 °C
View Scheme
C72H112INO13Si2

C72H112INO13Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 110 percent / C8K-ZnCl2-AgOAc / tetrahydrofuran / 1 h / 0 °C
2: 100 percent / dimethyl dioxirane / acetone / 2.17 h / -50 - -26 °C
3: 10.5 mg / aq. HF / acetonitrile / 10 h / 20 °C
View Scheme
C72H113NO14Si2

C72H113NO14Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 88 percent / triphenylphosphine; imidazole; iodine / toluene / 0.5 h / 70 °C
2: 110 percent / C8K-ZnCl2-AgOAc / tetrahydrofuran / 1 h / 0 °C
3: 100 percent / dimethyl dioxirane / acetone / 2.17 h / -50 - -26 °C
4: 10.5 mg / aq. HF / acetonitrile / 10 h / 20 °C
View Scheme
C80H121NO15Si2

C80H121NO15Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 92 percent / DDQ / CH2Cl2; H2O / 0.83 h / 20 °C
2: 88 percent / triphenylphosphine; imidazole; iodine / toluene / 0.5 h / 70 °C
3: 110 percent / C8K-ZnCl2-AgOAc / tetrahydrofuran / 1 h / 0 °C
4: 100 percent / dimethyl dioxirane / acetone / 2.17 h / -50 - -26 °C
5: 10.5 mg / aq. HF / acetonitrile / 10 h / 20 °C
View Scheme
C80H123NO16Si2

C80H123NO16Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 21.0 mg / Et3N; methyl-2-chloropyridinium iodide / CH2Cl2 / 14 h / 20 °C
2: 92 percent / DDQ / CH2Cl2; H2O / 0.83 h / 20 °C
3: 88 percent / triphenylphosphine; imidazole; iodine / toluene / 0.5 h / 70 °C
4: 110 percent / C8K-ZnCl2-AgOAc / tetrahydrofuran / 1 h / 0 °C
5: 100 percent / dimethyl dioxirane / acetone / 2.17 h / -50 - -26 °C
6: 10.5 mg / aq. HF / acetonitrile / 10 h / 20 °C
View Scheme
C63H93NO13Si

C63H93NO13Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
2: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
3: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
4: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
5: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
6: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C63H92INO12Si

C63H92INO12Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
2: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
3: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C63H93NO13Si

C63H93NO13Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
2: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
3: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
4: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C63H93NO14Si

C63H93NO14Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 6 steps
1: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
2: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
3: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
4: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
5: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
6: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C63H95NO14Si

C63H95NO14Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
2: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
3: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
4: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
5: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
6: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
7: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C63H91NO13Si

C63H91NO13Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
2: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
3: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
4: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
5: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C68H105NO15Si

C68H105NO15Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 12 steps
1: NaHCO3, KBr, 4-methoxy-2,2,6,6-tetramethylpiperidinyloxy free radical, NaOCl / CH2Cl2 / 1.33 h / 0 °C
2: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
3: 495 mg / diethyl ether
4: Dess-Martin periodinane / CH2Cl2 / 1 h
5: LiOH*H2O / tetrahydrofuran / 0.5 h
6: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
7: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
8: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
9: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
10: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
11: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
12: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
Multi-step reaction with 10 steps
1: NaHCO3, KBr, 4-methoxy-2,2,6,6-tetramethylpiperidinyloxy free radical, NaOCl / CH2Cl2 / 1.33 h / 0 °C
2: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
3: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1 h, 2) THF, 0 deg C, 1 h
4: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
5: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
6: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
7: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
8: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
9: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
10: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C69H106INO12Si2

C69H106INO12Si2

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
2: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C68H103NO15Si

C68H103NO15Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 11 steps
1: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
2: 495 mg / diethyl ether
3: Dess-Martin periodinane / CH2Cl2 / 1 h
4: LiOH*H2O / tetrahydrofuran / 0.5 h
5: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
6: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
7: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
8: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
9: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
10: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
11: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
Multi-step reaction with 9 steps
1: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
2: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1 h, 2) THF, 0 deg C, 1 h
3: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
4: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
5: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
6: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
7: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
8: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
9: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C68H101NO16Si

C68H101NO16Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 7 steps
1: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
2: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
3: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
4: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
5: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
6: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
7: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C68H103NO16Si

C68H103NO16Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 10 steps
1: 495 mg / diethyl ether
2: Dess-Martin periodinane / CH2Cl2 / 1 h
3: LiOH*H2O / tetrahydrofuran / 0.5 h
4: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
5: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
6: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
7: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
8: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
9: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
10: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
Multi-step reaction with 8 steps
1: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1 h, 2) THF, 0 deg C, 1 h
2: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
3: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
4: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
5: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
6: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
7: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
8: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C69H105NO16Si

C69H105NO16Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 9 steps
1: LiOH*H2O / tetrahydrofuran; H2O / 5 h / Ambient temperature
2: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1 h, 2) THF, 0 deg C, 1 h
3: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
4: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
5: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
6: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
7: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
8: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
9: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
Multi-step reaction with 9 steps
1: Dess-Martin periodinane / CH2Cl2 / 1 h
2: LiOH*H2O / tetrahydrofuran / 0.5 h
3: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
4: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
5: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
6: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
7: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
8: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
9: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C69H103NO16Si

C69H103NO16Si

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 8 steps
1: LiOH*H2O / tetrahydrofuran / 0.5 h
2: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
3: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
4: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
5: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
6: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
7: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
8: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
C80H133NO15Si3

C80H133NO15Si3

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 13 steps
1: 71 percent / TBAF / tetrahydrofuran / 2 h
2: NaHCO3, KBr, 4-methoxy-2,2,6,6-tetramethylpiperidinyloxy free radical, NaOCl / CH2Cl2 / 1.33 h / 0 °C
3: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
4: 495 mg / diethyl ether
5: Dess-Martin periodinane / CH2Cl2 / 1 h
6: LiOH*H2O / tetrahydrofuran / 0.5 h
7: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1h, 2) THF, 0 deg C, 1 h
8: 47.3 mg / 2-chloro-1-methylpyridinium iodide, NET3 / CH2Cl2 / 6 h / Heating
9: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
10: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
11: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
12: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
13: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
Multi-step reaction with 11 steps
1: 71 percent / TBAF / tetrahydrofuran / 2 h
2: NaHCO3, KBr, 4-methoxy-2,2,6,6-tetramethylpiperidinyloxy free radical, NaOCl / CH2Cl2 / 1.33 h / 0 °C
3: NaH2PO4, NaClO2 / 2-methyl-propan-2-ol; H2O; various solvent(s) / 2 h
4: 1) TESOTf, 2,6-lutidine, 2) TBAF, AcOH / 1) CH2Cl2, 0 deg C, 1 h, 2) THF, 0 deg C, 1 h
5: 1) 2-chloro-1-methylpyridinium iodide, NEt3, 2) NEt3 / 1) CH2Cl2, reflux, 17 h, 2) EtOH, 5 h
6: 81 percent / Dess-Martin periodinane / CH2Cl2 / 3 h / Ambient temperature
7: 84 percent / L-Selectride / tetrahydrofuran / 0.5 h / -78 °C
8: 83 percent / I2, PPh3, imidazole / toluene / 0.5 h / 75 °C
9: 74 percent / 1) KHMDS / tetrahydrofuran; toluene / 1) -78 deg C, 30 min, 2) 30 min
10: 67 percent / graphite, potassium, ZnCl2, AgOAc / tetrahydrofuran / 1.5 h / Ambient temperature
11: 1) dimethyldioxirane, 2) 40percent HF / 1) acetone, CH2Cl2, -45 deg C -> -25 deg C, 1 h; -25 deg C -> 0 deg C, 1 h, 2) MeCN, 6 h
View Scheme
(9RS,22S)-14-<(tert-butyldimethylsilyl)oxy>-9,22-tetrahydro-24,32-bis<(triisopropylsilyl)oxy>-FK506
128685-16-5, 128777-66-2

(9RS,22S)-14-<(tert-butyldimethylsilyl)oxy>-9,22-tetrahydro-24,32-bis<(triisopropylsilyl)oxy>-FK506

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: 82 percent / Dess-Martin periodinane / CH2Cl2 / 15 h / Ambient temperature
2: 73 percent / aq. HF / acetonitrile / 18 h / Ambient temperature
View Scheme
tacrolimus

tacrolimus

Tacrolimus
104987-11-3

Tacrolimus

Conditions
ConditionsYield
With polymer resin accoring to the invention In methanol; acetone`; water Purification / work up;
triisopropylsilyl trifluoromethanesulfonate
80522-42-5

triisopropylsilyl trifluoromethanesulfonate

Tacrolimus
104987-11-3

Tacrolimus

C62H109NO12Si2
123747-39-7

C62H109NO12Si2

Conditions
ConditionsYield
With 2,6-dimethylpyridine In dichloromethane 1) 0 deg C, 1,5 h, 2) 25 deg C, 16 h;99%
Tacrolimus
104987-11-3

Tacrolimus

2-propenamide
79-06-1

2-propenamide

C45H70N2O13
1190108-68-9

C45H70N2O13

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In 1,2-dichloro-benzene at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;99%
Tacrolimus
104987-11-3

Tacrolimus

acrylic acid
79-10-7

acrylic acid

C45H69NO14
1190108-69-0

C45H69NO14

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In 1,2-dichloro-benzene at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;99%
With Hoveyda-Grubbs catalyst second generation In 1,2-dichloro-ethane at 85℃; for 1h; Inert atmosphere; Sealed tube; Microwave irradiation;96%
With Hoveyda-Grubbs catalyst second generation In 1,2-dichloro-ethane at 85℃; for 1h; Inert atmosphere; Sealed tube;96%
Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane for 0.25h; UV-irradiation;99%
2-[(tert-butoxycarbonyl)amino]-1-ethanethiol
67385-09-5

2-[(tert-butoxycarbonyl)amino]-1-ethanethiol

Tacrolimus
104987-11-3

Tacrolimus

C51H84N2O14S

C51H84N2O14S

Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane at 20℃; for 0.25h; Solvent; Reagent/catalyst; UV-irradiation;98%
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane at 23℃; for 0.25h; Inert atmosphere; Irradiation;96%
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane at 23℃; for 0.25h; UV-irradiation; Inert atmosphere;96%
Tacrolimus
104987-11-3

Tacrolimus

3-mercaptopropionic acid
107-96-0

3-mercaptopropionic acid

C47H75NO14S

C47H75NO14S

Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane for 0.25h; Reagent/catalyst; UV-irradiation;98%
methanol
67-56-1

methanol

Tacrolimus
104987-11-3

Tacrolimus

C45H73NO13
133523-40-7

C45H73NO13

Conditions
ConditionsYield
With zinc(II) chloride for 3h; Ambient temperature;97%
for 3h; Heating;82%
Tacrolimus
104987-11-3

Tacrolimus

acrylic acid methyl ester
292638-85-8

acrylic acid methyl ester

C46H71NO14

C46H71NO14

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In 1,2-dichloro-benzene at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;97%
Tacrolimus
104987-11-3

Tacrolimus

tert-butyldimethylsilyl chloride
18162-48-6

tert-butyldimethylsilyl chloride

24,33-Bis-(t.butyl-dimethylsilyl)-FK 506
133941-75-0

24,33-Bis-(t.butyl-dimethylsilyl)-FK 506

Conditions
ConditionsYield
With 1H-imidazole In N,N-dimethyl-formamide96.7%
With 1H-imidazole In N,N-dimethyl-formamide Ambient temperature;
Tacrolimus
104987-11-3

Tacrolimus

Cysteamine
60-23-1

Cysteamine

C46H76N2O12S

C46H76N2O12S

Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In methanol for 0.25h; UV-irradiation;96%
Tacrolimus
104987-11-3

Tacrolimus

acrylic acid
79-10-7

acrylic acid

C45H69NO14

C45H69NO14

Conditions
ConditionsYield
With Hoveyda-Grubbs catalyst second generation In 1,2-dichloro-ethane at 85℃; for 1h; Inert atmosphere; Microwave irradiation;96%
t-butyldimethylsiyl triflate
69739-34-0

t-butyldimethylsiyl triflate

Tacrolimus
104987-11-3

Tacrolimus

24,33-Bis-(t.butyl-dimethylsilyl)-FK 506
133941-75-0

24,33-Bis-(t.butyl-dimethylsilyl)-FK 506

Conditions
ConditionsYield
With 2,6-dimethylpyridine In dichloromethane at 0℃; for 1h; Inert atmosphere;95%
C6H12N4OS
1277177-82-8

C6H12N4OS

Tacrolimus
104987-11-3

Tacrolimus

C50H81N5O13S

C50H81N5O13S

Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In dichloromethane for 0.25h; UV-irradiation;95%
L-Cysteine
52-90-4

L-Cysteine

Tacrolimus
104987-11-3

Tacrolimus

C47H76N2O14S

C47H76N2O14S

Conditions
ConditionsYield
With 2,2-dimethoxy-2-phenylacetophenone In methanol; water for 0.25h; UV-irradiation;95%
With 2,2-dimethoxy-2-phenylacetophenone In methanol; water at 23℃; for 0.25h; Inert atmosphere; UV-irradiation;92%
succinic acid anhydride
108-30-5

succinic acid anhydride

Tacrolimus
104987-11-3

Tacrolimus

C48H73NO15

C48H73NO15

Conditions
ConditionsYield
With Novozym SP435 In toluene at 45℃; for 80h; Inert atmosphere; Schlenk technique;95%
Conditions
ConditionsYield
With L-Selectride In tetrahydrofuran at -78℃; for 1.5h;90%
With tetramethylammonium triacetoxyborohydride In acetic acid; acetonitrile at -5 - 0℃; for 5h;25%
Multi-step reaction with 3 steps
1: imidazole / dimethylformamide
2: 66 percent / tetramethylammonium triacetoxyborohydride / acetonitrile; acetic acid / 5 h / -5 - 0 °C
3: 87 percent / 40percent aq. HF / acetonitrile / 2 h / 10 °C
View Scheme
Tacrolimus
104987-11-3

Tacrolimus

acryloyl chloride
814-68-6

acryloyl chloride

C45H68ClNO13
1190108-71-4

C45H68ClNO13

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In isopropyl alcohol at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;88%
Tacrolimus
104987-11-3

Tacrolimus

C45H71NO12
133941-69-2

C45H71NO12

Conditions
ConditionsYield
palladium diacetate In dichloromethane Ambient temperature;87%
4-bromo-N-methylaniline
6911-87-1

4-bromo-N-methylaniline

Tacrolimus
104987-11-3

Tacrolimus

C51H76N2O12

C51H76N2O12

Conditions
ConditionsYield
With palladium diacetate; potassium carbonate; triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 20h; Inert atmosphere; Schlenk technique;82%
With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 20h; Heck Reaction; Inert atmosphere; Schlenk technique;62%
methanol
67-56-1

methanol

Tacrolimus
104987-11-3

Tacrolimus

C45H71NO13
124125-40-2

C45H71NO13

Conditions
ConditionsYield
With lead(IV) acetate81%
Tacrolimus
104987-11-3

Tacrolimus

(E)-(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-12-[(E)-2-((1R,3R,4R)-3,4-dimethoxy-cyclohexyl)-1-methyl-vinyl]-1-hydroxy-14,23,25-trimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone
124554-15-0

(E)-(1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-12-[(E)-2-((1R,3R,4R)-3,4-dimethoxy-cyclohexyl)-1-methyl-vinyl]-1-hydroxy-14,23,25-trimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-aza-tricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone

Conditions
ConditionsYield
With boron trifluoride diethyl etherate In dichloromethane at 0 - 5℃;80%
Tacrolimus
104987-11-3

Tacrolimus

(E)-(8S,11S,12R,13S,16R,20S,22S,23R,24S,26R)-16-Allyl-1,13-dihydroxy-11-[(E)-2-((1R,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-22,24-dimethoxy-12,18,20,26-tetramethyl-10,28-dioxa-3-aza-tricyclo[21.4.1.03,8]octacos-17-ene-2,9,15,27-tetraone

(E)-(8S,11S,12R,13S,16R,20S,22S,23R,24S,26R)-16-Allyl-1,13-dihydroxy-11-[(E)-2-((1R,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl)-1-methyl-vinyl]-22,24-dimethoxy-12,18,20,26-tetramethyl-10,28-dioxa-3-aza-tricyclo[21.4.1.03,8]octacos-17-ene-2,9,15,27-tetraone

Conditions
ConditionsYield
With zinc(II) chloride In dichloromethane for 15h; Ambient temperature;80%
4-ethenylbenzoic acid
1075-49-6

4-ethenylbenzoic acid

Tacrolimus
104987-11-3

Tacrolimus

C51H73NO14
1190108-85-0

C51H73NO14

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In 1,2-dichloro-benzene at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;79%
4-vinyl benzylamine
1520-21-4

4-vinyl benzylamine

Tacrolimus
104987-11-3

Tacrolimus

C50H74N2O12
1190108-83-8

C50H74N2O12

Conditions
ConditionsYield
With tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidine][benzylidene]ruthenium(II) dichloride In 1,2-dichloro-benzene at 150℃; for 0.0833333h; olefin cross-metathesis reaction; Microwave irradiation; Inert atmosphere;79%
Tacrolimus
104987-11-3

Tacrolimus

3-fluoro-4-iodopyridine
22282-75-3

3-fluoro-4-iodopyridine

C49H71FN2O12

C49H71FN2O12

Conditions
ConditionsYield
With palladium diacetate; triethylamine; tris-(o-tolyl)phosphine In N,N-dimethyl-formamide at 100℃; for 24h; Heck Reaction; Inert atmosphere; Schlenk technique;78%
trimethylsilyl cyanide
7677-24-9

trimethylsilyl cyanide

Tacrolimus
104987-11-3

Tacrolimus

C45H70N2O12
133523-41-8

C45H70N2O12

Conditions
ConditionsYield
With potassium cyanide; 18-crown-6 ether In benzene at 23℃; for 20h;76%
Tacrolimus
104987-11-3

Tacrolimus

(3R,5S,6R)-6-[(5E,13E)-(1S,3S,7R,10S,11R,12S)-7-Allyl-10,12-dihydroxy-14-((1R,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl)-1-methoxy-3,5,11,13-tetramethyl-8-oxo-tetradeca-5,13-dienyl]-5-methoxy-3-methyl-tetrahydro-pyran-2-one

(3R,5S,6R)-6-[(5E,13E)-(1S,3S,7R,10S,11R,12S)-7-Allyl-10,12-dihydroxy-14-((1R,3R,4R)-4-hydroxy-3-methoxy-cyclohexyl)-1-methoxy-3,5,11,13-tetramethyl-8-oxo-tetradeca-5,13-dienyl]-5-methoxy-3-methyl-tetrahydro-pyran-2-one

Conditions
ConditionsYield
With tetra-n-butylammonium cyanide In tetrahydrofuran; water at 5℃; for 2h;76%

104987-11-3Relevant articles and documents

Synthesis and characterization of an epimer of tacrolimus, an immunosuppressive drug

Skytte, Dorthe M.,Frydenvang, Karla,Hansen, Liselotte,Nielsen, Peter G.,Jaroszewski, Jerzy W.

, p. 776 - 779 (2010)

8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products.

Characterization of FK506 biosynthetic intermediates involved in post-PKS elaboration

Ban, Yeon Hee,Shinde, Pramod B.,Hwang, Jae-Yeon,Song, Myoung-Chong,Kim, Dong Hwan,Lim, Si-Kyu,Sohng, Jae Kyung,Yoon, Yeo Joon

, p. 1091 - 1098 (2013/07/26)

The post-PKS modification steps of FK506 biosynthesis include C9-oxidation and 31-O-methylation, but the sequence of these reactions and the exact route have remained unclear. This study details the post-PKS modification pathways in FK506 biosynthesis thr

A PROCESS FOR PURIFICATION OF MACROLIDES

-

Page/Page column 5-6, (2008/06/13)

The present invention relates to a process for separating a macrolide from a mixture comprising homologs, analogs or isomers thereof by using silver-impregnated silica gel chromatography.

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